Methods of treating and/or preventing cardiovascular disease

ABSTRACT

Methods of treating or preventing cardiovascular disease and/or inflammatory disease in mammalian subjects comprising the administration of the novel formulations disclosed herein are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of PCT Application No.PCT/IB2014/001201, filed Apr. 16, 2014, which claims the benefit of U.S.Provisional Application No. 61/812,514, filed Apr. 16, 2013, and EPPatent Application No. 13194505.7, filed Nov. 26, 2013, the entirecontents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Colchicine, chemical name(−)-N-[(7S,12aS)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]-acetamide,is an alkaloid found in extracts of Colchicum autumnale, Gloriosasuperba, and other plants. It is a microtubule-disrupting agent used inthe treatment of conditions that may be treated, relieved or preventedwith anti-inflammatory treatment.

Colchicine is well recognized as a valid therapy in acute flares ofgouty arthritis, familial Mediterranean fever (FMF), Behçet's disease.It has also been used to treat many inflammatory disorders prone tofibrosis. In the recent past, colchicine has been proposed to beeffective in therapy in cardiovascular diseases.

In particular, colchicine has been proposed as a first treatment optionfor recurrent pericarditis (class I indication) and optional for acutepericarditis (class IIa indication) in the 2004 European guidelines onthe management of pericardial diseases (Maisch et al., Guidelines on theDiagnosis and Management of Pericardial Diseases, Eur Heart J., 2004,25, 916-928).

Imazio el al. (Circulation, 2005, 112 (13), 2012-2016) showed thatcolchicine was effective for the treatment and the prevention ofrecurrent pericarditis in a prospective, randomized, open-label designedstudy of 120 patients with a first episode of acute pericarditis(idiopathic, viral, postpericardiotomy syndromes, and connective tissuediseases), who were randomly assigned to conventional treatment withaspirin or conventional treatment plus colchicine (1.0 to 2.0 mg for thefirst day and then 0.5 to 1.0 mg/day for 3 months). The primary endpoint was recurrence rate, which was significantly reduced from 32.3%down to 10.7% at 18 months in the colchicine group (p=0.004).

Further, the same group showed that colchicine could be efficient afterconventional treatment failure to manage acute pericarditis (Imazio atal., Arch InternMed, 2005, 165 (17), 1987-91). In a prospective,randomized, open-label design, 84 consecutive patients with a firstepisode of recurrent pericarditis were randomly assigned to receiveconventional treatment with aspirin alone or conventional treatment pluscolchicine (1.0-2.0 mg the first day and then 0.5-1.0 mg/d for 6months). The primary end point was the recurrence rate, which wassignificantly decreased in the colchicine group (actuarial rates at 18months were 24.0% vs 50.6% with conventional treatment).

It has also been shown that colchicine is effective for secondaryprevention of recurrent pericarditis Imazio et al., Ann. Intern. Med.,2011, 155 (7), 409-14). Colchicine has also been proposed to reducepostpericardiotomy reactions revealed as pericarditis (Imazio et al.,Am. Heart J., 2011, 162 (3), 527-532; Meurin and Tabet, Arch.Cardiovasc. Dis., 2011, 104 (8-9), 425-427).

Colchicine for the treatment of post-pericardiotomy syndrome (PPS) wastested for the first time in a preliminary prospective, open-label,randomized trial of colchicine (1.5 mg/day) compared with placebobeginning on the third post-operative day in 163 patients who underwentcardiac surgery (Finkelstein et al., Herz, 2002 27, 791-194).

The effectiveness of colchicine for the prevention of PPS has also beenshown in a multicentre, double-blind, randomized trial, in which 360patients (mean age 65.7+12.3 years, 66% males), 180 in each treatmentarm, were randomized to receive placebo or colchicine (1.0 mg twicedaily for the first day followed by a maintenance dose of 0.5 mg twicedaily for 1 month in patients ≧70 kg, and halved doses for patients, 70kg or intolerant to the highest dose) on the third post-operative day(Imazio et al., European Heart Journal, 2010, 31, 2749-2754).

In another study, the effectiveness of colchicine has been shown forcardiovascular disease. In this clinical trial with a prospective,randomized, observer-blinded endpoint design, 532 patients with stablecoronary disease receiving aspirin and/or clopidogrel (93%) and statins(95%) were randomly assigned colchicine 0.5 mg/day or no colchicine andfollowed for a median of 3 years (Nidorf et al., JACC, 2013, 61 (4),404-410). This study showed that colchicine 0.5 mg/day administered inaddition to statins and other standard secondary prevention therapiesappeared effective for the prevention of cardiovascular events inpatients with stable coronary disease.

For the treatment of gout, the recommended dose of colchicine (COLCRYS®)is 1.8 mg/day in one or multiple doses in one hour. For adults withgout, treatment is initiated with a dose of 1.2 mg at the first sign ofsymptoms followed by 0.6 mg one hour later. (Physician's Desk Reference,68th ed., (2014)).

COLCRYS® is an immediate release formulation. Adverse effects associatedwith the administration of COLCRYS® include, but are not limited to,nausea, vomiting, abdominal pain, diarrhea, hair loss, weakness, nerveirritation, severe anemia, low white blood counts, and low platelets(Physician's Desk Reference, 68th ed., (2014)).

The instant invention addresses these and other needs by providing amodified formulation of colchicine characterized by a sustained releaseof an active ingredient. This invention additionally provides aneffective, once-daily dosage form of colchicine or salts thereof, whichmay improve patient compliance and also may reduce some of the sideeffects of colchicine compared to the current or higher daily doses ofimmediate release colchicine formulations.

BRIEF SUMMARY OF THE INVENTION

According to aspects of the invention illustrated herein, there isprovided a method of treating and/or preventing cardiovascular diseasein a patient, the method consisting of orally administering a sustainedrelease formulation comprising not more than 0.60 mg colchicine to ahuman patient, wherein the colchicine is administered once a day,thereby treating and/or preventing the cardiovascular disease in thepatient.

According to aspects of the invention illustrated herein, there isprovided a method of treating a patient having a cardiovascular disease,the method consisting of: orally administering a sustained releaseformulation comprising not more than 0.60 mg colchicine to a humanpatient once daily, wherein the sustained release formulation provides amaximum colchicine blood plasma concentration (Cmax) in a range of about1.0 to about 2.0 ng/mL, and a time after the first administration atwhich Cmax is reached (Tmax) of about 1.2 to about 2.0 hr.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawings will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 shows the dissolution profiles for colchicine sustained-releaseformulations containing 10%, 15% and 20%, respectively, of an exemplaryretarding agent.

FIG. 2 shows the dissolution profiles for colchicine sustained-releaseformulation containing 30% of an exemplary retarding agent and tablethardnesses of 50N and 130N, respectively.

FIG. 3 shows the dissolution profiles for colchicine sustained-releaseformulations according to FIGS. 1 and 2.

FIG. 4 shows the dissolution profile for a colchicine sustained-releaseformulation containing 0% of an exemplary retarding agent.

FIG. 5 shows the dissolution profile for a colchicine sustained-releaseformulation containing 25% of an exemplary retarding agent.

FIG. 6 shows the dissolution profile for colchicine formulationcontaining 0%, 23.3%, 26.6% and 30% of an exemplary retarding agent.

FIGS. 7A, 7B, 7C and 7D show plasma colchicine levels (ng/mL) as afunction of time (hrs) for colchicine formulations according to FIG. 6.

FIG. 8 shows plasma colchicine levels (ng/mL) as a function of time(hrs) for colchicine formulations according to FIG. 6.

FIG. 9 shows the levels of colchicine in neutrophils on Day 1 and Day 10for colchicine formulations according to FIG. 6.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

For the purposes of this invention, the term “colchicine” includescolchicine or any pharmaceutically acceptable salts thereof.

“Pharmaceutically acceptable” means that which is generally safe,non-toxic and neither biologically nor otherwise undesirable andincludes that which is acceptable for veterinary use as well as humanpharmaceutical use.

“Pharmaceutically acceptable salts” includes derivatives of colchicine,wherein the colchicine is modified by making acid or base addition saltsthereof, and further refers to pharmaceutically acceptable solvates,including hydrates, and co-crystals of such compounds and such salts.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid addition salts of basic residuessuch as amines; alkali or organic addition salts of acidic residues; andthe like, and combinations comprising one or more of the foregoingsalts. The pharmaceutically acceptable salts include non-toxic salts andthe quaternary ammonium salts of the colchicine. For example, non-toxicacid salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric andthe like; other acceptable inorganic salts include metal salts such assodium salt, potassium salt, cesium salt, and the like; and alkalineearth metal salts, such as calcium salt, magnesium salt, and the like,and combinations comprising one or more of the foregoing salts.Pharmaceutically acceptable organic salts includes salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic,esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC—(CH2)n-COOHwhere n is 0-4, and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, and thelike; and amino acid salts such as arginate, asparaginate, glutamate,and the like; and combinations comprising one or more of the foregoingsalts; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′ dibenzylethylenediamine salt, and the like;and amino acid salts such as arginate, asparaginate, glutamate, and thelike; and combinations comprising one or more of the foregoing salts.All forms of such derivatives of colchicine are contemplated herein,including all crystalline, amorphous, and polymorph forms. Specificcolchicine salts include colchicine hydrochloride, colchicinedihydrochloride, and co-crystals, hydrates or solvates thereof.

“Pharmacokinetic parameters” describe the in vivo characteristics of anactive agent (or a metabolite or a surrogate marker for the activeagent) over time, such as plasma concentration (C), Cmax, Cn, C24, Tmax,and AUC. “Cmax” is the measured plasma concentration of the active agentat the point of maximum, or peak, concentration. “Cmin” is the measuredplasma concentration of the active agent at the point of minimumconcentration. “Cn” is the measured plasma concentration of the activeagent at about n hours after administration. “C24” is the measuredplasma concentration of the active agent at about 24 hours afteradministration. The term “Tmax” refers to the time at which the measuredplasma concentration of the active agent is the highest afteradministration of the active agent. “AUC” is the area under the curve ofa graph of the measured plasma concentration of an active agent vs.time, measured from one time point to another time point. For exampleAUC0-t is the area under the curve of plasma concentration versus timefrom time 0 to time t, where t can be the last time point withmeasurable plasma concentration for an individual formulation. TheAUC0-∞ or AUC0-INF is the calculated area under the curve of plasmaconcentration versus time from time 0 to time infinity. In steady-statestudies, AUC0-τ is the area under the curve of plasma concentration overthe dosing interval (i.e., from time 0 to time τ (tau), where tau is thelength of the dosing interval. Other pharmacokinetic parameters are theparameter Ke or Kel, the terminal elimination rate constant calculatedfrom a semi-log plot of the plasma concentration versus time curve; t½the terminal elimination half-life, calculated as 0.693/Kel; CL/Fdenotes the apparent total body clearance after administration,calculated as Total Dose/Total AUC∞; and Varea/F denotes the apparenttotal volume of distribution after administration, calculated as TotalDose/(Total AUC∞×Kel).

“Efficacy” means the ability of an active agent administered to apatient to produce a therapeutic effect in the patient.

“Bioavailability” means the extent or rate at which an active agent isabsorbed into a living system or is made available at the site ofphysiological activity. For active agents that are intended to beabsorbed into the bloodstream, bioavailability data for a givenformulation may provide an estimate of the relative fraction of theadministered dose that is absorbed into the systemic circulation.“Bioavailability” can be characterized by one or more pharmacokineticparameters.

A “dosage form” means a unit of administration of an active agent.Examples of dosage forms include tablets, capsules, injections,suspensions, liquids, emulsions, creams, ointments, suppositories,inhalable forms, transdermal forms, and the like.

An “immediate release formulation” refers to a formulation that releasesgreater than or equal to about 80% of the pharmaceutical agent in lessthan or equal to about 30 min.

For the purposes of this application, an enhancing agent (“enhancer”) isdefined as any non-pharmaceutically active ingredient that improves thetherapeutic potential of a formulation.

“Sustained release” is defined herein as release of a pharmaceuticalagent in a continuous manner over a prolonged period of time.

By “prolonged period of time” it is meant a continuous period of time ofgreater than about 1 hour, greater than about 4 hours, greater thanabout 8 hours, greater than about 12 hours, greater than about 16 hours,or up to more than about 24 hours.

As used herein, unless otherwise noted, “rate of release” or “releaserate” or “dissolution rate” of a drug refers to the quantity of drugreleased from a dosage form per unit time, e.g., milligrams of drugreleased per hour (mg/hr) or a percentage of a total drug dose releasedper hour. Drug release rates for dosage forms are typically measured asan in vitro rate of drug release, i.e., a quantity of drug released fromthe dosage form per unit time measured under appropriate conditions andin a suitable fluid. The release rates referred to herein are determinedby placing a dosage form to be tested in a medium in an appropriatedissolution bath. Aliquots of the medium, collected at pre-setintervals, are then injected into a chromatographic system fitted withan appropriate detector to quantify the amounts of drug released duringthe testing intervals.

Side effect is defined herein as a secondary and usually adverse effectof a drug.

Terms such as “treating” or “treatment” or “to treat” or “alleviating”or “to alleviate” refer to both 1) therapeutic measures that cure, slowdown, lessen symptoms of, reverse, and/or halt progression of adiagnosed pathologic condition or disorder and 2) prophylactic orpreventative measures that prevent and/or slow the development of atargeted pathologic condition or disorder. Thus those in need oftreatment include those already with the disorder; those prone to havethe disorder; and those in whom the disorder is to be prevented.Beneficial or desired clinical results include, but are not limited to,alleviation of symptoms, diminishment of extent of disease, stabilized(i.e., not worsening) state of disease, delay or slowing of diseaseprogression, amelioration or palliation of the disease state, andremission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment. Those in need oftreatment include those already with the condition or disorder as wellas those prone to have the condition or disorder or those in which thecondition or disorder is to be prevented.

By “subject” or “individual” or “animal” or “patient” or “mammal,” ismeant any subject, particularly a mammalian subject, for whom diagnosis,prognosis, or therapy is desired. Mammalian subjects include humans,domestic animals, farm animals, and zoo, sports, or pet animals such asdogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows,bears, and so on. The meaning of the terms “eukaryote”, “animal”,“mammal”, etc. is well known in the art and can, for example, be deducedfrom Wehner and Gehring (1995; Thieme Verlag). In the context of thisinvention, it is also envisaged that animals are to be treated which areeconomically, agronomically or scientifically important. Scientificallyimportant organisms include, but are not limited to, mice, rats, andrabbits. Non-limiting examples of agronomically important animals aresheep, cattle and pigs, while, for example, cats and dogs may beconsidered as economically important animals. In one embodiment, thesubject/patient is a mammal; in another embodiment, the subject/patientis a human or a non-human mammal (such as, e.g., a guinea pig, ahamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, anape, a marmoset, a baboon, a gorilla, a chimpanzee, an orang-utan, agibbon, a sheep, cattle, or a pig); most preferably, the subject/patientis a human.

II. Colchicine

In the following, colchicine used according to the present inventionwill be described in detail. The chemical structure of colchicine(ChemID 2012) is as follows:

The chemical name of colchicine is:N[5,6,7,9-tetrahydro-1,2,3,10-tetratmethoxy9-oxobenzo[a]heptalen-7-yl],(S)-acetamide; molecular formula: C₂₂H₂₅NO₆;CAS number: 64-86-8.

Colchicine is an anti-inflammatory drug with a long history in humanmedicine, used for the symptomatic treatment of inflammatory diseases,most prominently gout. It is a natural product which can be extractedfrom two plants of the lily family, Colchicum autumnale and Gloriosasuperba. Colchicine is a tricyclic alkaloid and has a molecular mass of399.437. The active ingredient colchicine as well as its tabletformulation is listed in various national and internationalpharmacopeias such as the United States Pharmacopeia (USP).

The positive effect of its plant source in the treatment of rheumatismand swelling was described first already around 1500 B.C. in Egypt. Itsuse in gout was first described around 1500 years ago (Graham andRoberts, 1953, Ann Rheum Dis 12(1): 16-9). Today, the therapeutic valueof colchicine is well established in a number of inflammatory diseasesand approved by FDA for the prophylaxis and treatment of acute goutflares and familial Mediterranean fever (FMF). Other importantestablished, though off-label uses are amongst others, Behçet's diseaseand recurrent pericarditis. In all known indications, it is generallyadministered orally as solid tablets in strengths of 0.5-0.6 mg/tablet(e.g. Europe and United States, respectively). The pharmacotherapeuticmechanism of action of colchicine in diverse disorders is not fullyunderstood, though it is known that the drug accumulates preferentiallyin leucocytes, particularly neutrophils which is important for itstherapeutic effect. Three major interactions of colchicine with specificproteins modulate its pharmacokinetics: tubulin, cytochrome P450 3A4(CYP3A4), and P-glycoprotein. It is assumed that most therapeuticeffects of the drug are related to its capacity to bind to β-tubulin,thus inhibiting self-assembly and polymerization of microtubules.Availability of tubulin is essential for several cellular functions suchas mitosis. Therefore colchicine effectively functions as a “mitoticpoison” or spindle poison. By inhibiting microtubule self-assembly,colchicine interferes with many cellular functions involved in theimmune response such as modulation of the production of chemokineschemokines and prostanoids and inhibition of neutrophil and endothelialcell adhesion molecules. Eventually it decreases neutrophildegranulation, chemotaxis and phagocytosis, thus reducing the initiationand amplification of inflammation. Colchicine also inhibits uric acidcrystal deposition (a process important to the genesis of gout), whichis enhanced by a low pH in the tissues, probably by inhibiting oxidationof glucose and subsequent lactic acid reduction in leukocytes (Imazio,Brucato et al. 2009, Eur Heart J, 30(5): 532-9; Cocco, Chu et al. 2010,Eur J Intern Med, 21(6): 503-8; Stanton, Gernert et al. 2011, Med ResRev, 31(3): 443-81). In the management of pericarditis, colchicineexcerpts its therapeutic effect by suppressing the acute pericardialinflammation. However, the exact cellular and molecular mechanisms ofhow colchicine relieves pain and inflammation in acute pericarditis andprevents recurrences are not fully understood.

Colchicine in the context of the present invention can be used for theprevention and/or treatment of cardiovascular diseases and/orinflammatory diseases.

III. Sustained Release Formulations

The present invention additionally provides a sustained releasecolchicine formulation for the treatment or prevention of acardiovascular disease and/or an inflammatory disorder in a subjectwherein colchicine is released from the formulation at a sustained ratealong a pre-determined or desired release profile. Such release isachieved by incorporation into the formulation of an extended releasecomponent and an optional immediate release component. The colchicineformulation of the present invention may be formulated in a dosage formselected from a tablet, a pill, a capsule, a caplet, a troche, a sachet,a cachet, a pouch, sprinkles, or any other form suitable for oraladministration.

According to the present invention, colchicine as described herein(i.e., inter alia, in the form of a (pharmaceutical) composition) isadministered in the form of a sustained release preparation. Otherexpressions like “extended release”, “controlled release”, “modifiedrelease” or “delayed release” “preparation” or “formulation” areunderstood herein to have the same meaning as “sustained releasepreparation”. Such preparations can in principal be in any formconceivable to the skilled person and include pharmaceutical forms fororal (solid, semi-solid, liquid), dermal (dermal patch), sublingual,parenteral (injection), ophthalmic (eye drops, gel or ointment) orrectal (suppository) administration, as long as a sustained release isensured. In some embodiments, the sustained release formulation is not acontrolled release osmotic pump double layer tablet.

In accordance with the invention, sustained release preparationsencompass all pharmaceutical forms that create a steady drug releaseprofile making the drug substance available over an extended period oftime following application to the patient. Such an extended period oftime may be between 10, 20, 30, 40, 50 or 60 minutes and about 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or24 hours. Extended release may also be defined functionally as therelease of over 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99 percent (%)of colchicine after about 10, 20, 30, 40, 50 or 60 minutes and about 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23 or 24 hours. Extended release as used herein may also be defined asmaking colchicine available to the patient regardless of uptake, as somecolchicine may never be absorbed by the patient. Various extendedrelease dosage forms may be designed readily by one of skill in art asdisclosed herein to achieve delivery and sustained release of colchicineto the liver and/or both the small and large intestines, to only thesmall intestine, or to only the large intestine.

In some embodiments, sustained release preparations may be pHindependent. This allows such preparations to dissolve in almost anyenvironment. In other embodiments, sustained release preparations may bepH dependent. This allows release to be accomplished at some generallypredictable location in the lower intestinal tract more distal to thatwhich would have been accomplished if there had been no delayed releasealterations. A method for delay of release is, e.g., a coating. Anycoatings should be applied to a sufficient thickness such that theentire coating does not dissolve in the gastrointestinal fluids at pHbelow about 5, but does dissolve at pH about 5 and above. It is expectedthat any anionic polymer exhibiting a pH-dependent solubility profilecan be used as an enteric coating in the practice of the presentinvention to achieve delivery to the lower gastrointestinal tract.Polymers and compatible mixtures thereof may be used to provide thecoating for the delayed or the extended release of active ingredients,and some of their properties, include, but are not limited to: shellac,also called purified lac, a refined product obtained from the resinoussecretion of an insect. This coating dissolves in media of pH>7.

In some embodiments, sustained release preparations may be influenced bythe presence of alcohol in the body. The presence of alcohol is apatient's body can increase dissolution of the composition and can causeimmediate release of the entire dose. This effect is known as “dosedumping” and is dependent on the alcohol solubility of the materials.For sustained release preparations which contain a higher dose for slowrelease over 24 hours, for instance, this effect can have safetyconcerns and can even be life threatening.

To achieve a uniform or continuous rate of release, sustained releasepreparations may be prepared using time release hydrophilic matrices.These time release hydrophilic matrices are known in the field of drugformulations. For example, one such hydrophilic matrix is hydroxypropylmethylcellulose (HPMC) or Hypromellose. Hydrophilic matrices provide aninitial release of the drug product in the initial phase mainlytriggered by a rapid swelling of the surface of the matrix tablet,combined with an erosion process leading to an immediate release of thedrug substance distributed close to the surface of the tablet. In anembodiment, about 50%, about 45%, about 40%, about 35%, about 30%, about25%, about 20%, about 15%, or about 10% of the drug substance mayimmediately be released depending on the desired release profile. In anembodiment, at least about 20% of the drug substance may immediately bereleased. In another embodiment, at least about 20% of the drugsubstance may be released within about the first 30 minutes. As usedherein, the term “about” or “approximately” refers to a variation of 10%from the indicated values (e.g., 50%, 45%, 40%, etc.), or in case of arange of values, means a 10% variation from both the lower and upperlimits of such ranges. For instance, “about 50%” refers to a range ofbetween 45% and 55%. Within the initial swelling of the tablet surface agel formation of the hydrophilic matrix starts. This gelling preventsthe tablet core from dissolving and disintegrating immediately, therebyallowing the main part of the drug substances to dissolve slowly overtime within in this gel structure and diffuse into solution followingthe rules of Fick's law. The diffusion itself may be triggered in thisformulation approach by the concentration of the Hypromellose and theviscosity of the formed gel, defined over the molecular weight of theHypromellose. Therefore, drug release profiles can be modified byvarying different viscosity grades of Hypromellose or mixtures thereof.All corresponding formulation and process parameters achieving thepredicted release profile are common knowledge and can be adjusted usingactual development technologies e.g. formulation screenings, statisticaltrials designs.

In an embodiment, the substance responsible for sustained release of thecontrolled-release formulation can further mix with a binder. The binderis added to increase the mechanical strength of the granules and tabletsduring formation. Binders can be added to the formulation in differentways: (1) as a dry powder, which is mixed with other ingredients beforewet agglomeration, (2) as a solution, which is used as agglomerationliquid during wet agglomeration, and is referred to as a solutionbinder, and (3) as a dry powder, which is mixed with the otheringredients before compaction. In this form the binder is referred to asa dry binder. Solution binders are a common way of incorporating abinder into granules. In certain embodiments, the binder used in theformulation is in the form of a dry powder binder. Non-limiting examplesof binders useful for the core include hydrogenated vegetable oil,castor oil, paraffin, higher aliphatic alcohols, higher aliphatic acids,long chain fatty acids, fatty acid esters, wax-like materials such asfatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenatedfats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol,hydrophobic and hydrophilic polymers having hydrocarbon backbones, andmixtures thereof. Specific examples of water-soluble polymer bindersinclude modified starch, gelatin, polyvinylpyrrolidone, cellulosederivatives (such as for example hydroxypropyl methylcellulose (HPMC)and hydroxypropyl cellulose (HPC)), polyvinyl alcohol and mixturesthereof. In an embodiment, the binder is HPMC. In another embodiment,the binder is Hypromellose 6 mPa*s. In an embodiment, the binder can bepresent in an amount of from about 1% to about 30% by weight of theformulation.

In another embodiment of the invention, the sustained releaseformulation may include a disintegrant. A disintegrant refers to anagent used in pharmaceutical preparation of tablets, which causes themto disintegrate and release their medicinal substances on contact withmoisture. In an embodiment, the disintegrant may be water soluble tosupport the disintegration of a tablet in the stomach. Non-limitingexamples of disintegrants for use in the formulation include sucrose,lactose, in particular lactose monohydrate, trehalose, maltose, mannitoland sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodiumalginate, methacrylic acid DVB, cross-linked PVP, microcrystallinecellulose, polacrilin potassium, sodium starch glycolate, starch,pregelatinized starch and mixtures thereof. In at least one embodimentthe disintegrant is selected from microcrystalline cellulose (e.g.Avicel PH101), cross-linked polyvinylpyrrolidone (e.g. KOLLIDON® CL),cross-linked sodium carboxymethylcellulose (e.g. AC-DI-SOL™), starch orstarch derivatives such as sodium starch glycolate (e.g. EXPLOTAB®), orcombinations with starch (e.g. PRIMOJEL™), swellable ion-exchangeresins, such as AMBERLITE™ IRP 88, formaldehyde-casein (e.g. ESMASPRENG™), and mixtures thereof.

In another embodiment of the invention, the sustained releaseformulation may include a filling agent or filler. A filling agentrefers to an inert substance used as filler to create desired bulk, flowproperties, and compression characteristics in preparation of tablets.Non-limiting examples of filling agents for use in the formulationinclude sucrose, lactose, in particular lactose monohydrate, trehalose,maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone,alginic acid, sodium alginate, methacrylic acid DVB, cross-linked PVP,microcrystalline cellulose, polacrilin potassium, sodium starchglycolate, starch, pregelatinized starch and mixtures thereof. In anembodiment, lactose monohydrate is included as a filling agent in anamount of about 10% to about 80%, preferably about 59%, by weight of thetablet. In an embodiment, pregelatinized starch is included as a fillingagent in an amount of about 5% to about 50%, preferably about 7.5%, byweight of the tablet.

In another embodiment, the sustained release formulation of the presentinvention may include a release retarding agent for maintaining auniform release rate of the drug. Examples of retarding agents include,but are not limited to, cellulose ethers, cellulose esters, acrylic acidcopolymers, waxes, gums, glyceryl fatty acid esters and sucrose fattyacid esters. In one embodiment, the retarding agent is RETALAC®(Meggle), a spray agglomerated blend of 50 parts lactose monohydrate and50 parts hypromellose. The viscosity of hypromellose used herein mayrange from 6 mPa*s-100,000 mPa*s. In an embodiment, the viscosity ofhypromellose used is 4000 mPa*s. Adjusting the amount of retarding agentin the composition may alter the release rate of the drug. In oneembodiment, the retarding agent of the formulation of the presentinvention releases colchicine in a continuous and uniform manner and isadjusted in such a way that about 80% of the active ingredient isreleased in vitro in the predetermined period of time. By way ofexample, and by no means limiting the scope of the invention, the periodof time may be not more than 24 hours, not more than 16 hours, not morethan 12 hours, not more than 8 hours, not more than 6 hours, not morethan 4 hours, not more than 3.5 hours, or not more than 1.5 hoursdepending on desired attributes of the final product. It is understoodthat the release rate can vary based on whether the experiment isconducted in vitro or in vivo. Therefore, if the desired release rate isbetween about 1.5 to about 3.5 hours in vitro or between about 1.5 toabout 6 hours in vitro, the release rate under in vivo conditions,depending on the experimental conditions, may actually be different. Inan embodiment, the sustained release formulation of the presentinvention releases colchicine in a continuous and uniform manner in sucha way that about 80% of the active ingredient is released in vitro inbetween about 1.5 and about 3.5 hours.

In another embodiment, the sustained release formulation of the presentinvention may include a glidant. A glidant can be used to improve powderflow properties prior to and during tableting and to reduce caking.Suitable glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, talc, tribasic calcium phosphate andthe like. In one embodiment, talc is included as a glidant in an amountof about 0.05% to about 5%, preferably about 1%, by weight of thetablet.

In another embodiment, the sustained release formulation of the presentinvention may include a lubricant. Lubricants can be added topharmaceutical formulations to decrease any friction that occurs betweenthe solid and the die wall during tablet manufacturing. High frictionduring tableting can cause a series of problems, including inadequatetablet quality (capping or even fragmentation of tablets duringejection, and vertical scratches on tablet edges) and may even stopproduction. Accordingly, lubricants are added to certain tabletformulations of the present invention including certain embodiments ofthe formulation described herein. Non-limiting examples of lubricantsuseful for the core include glyceryl behenate, stearic acid,hydrogenated vegetable oils (such as hydrogenated cottonseed oil(STEROTEX®), hydrogenated soybean oil (STEROTEX® PIM) and hydrogenatedsoybean oil & castor wax (STEROTEX® K)), stearyl alcohol, leucine,polyethylene glycol (MW 1450, suitably 4000, and higher), magnesiumstearate, glyceryl monostearate, polyethylene glycol, ethylene oxidepolymers (for example, available under the registered trademarkCARBOWAX® from Union Carbide, Inc., Danbury, Conn.), sodium laurylsulfate, magnesium lauryl sulfate, sodium oleate, sodium stearylfumarate, DL-leucine, colloidal silica, mixtures thereof and others asknown in the art. In one embodiment, stearic acid is included as alubricant in an amount of about 0.05% to about 5%, preferably about 1%,by weight of the tablet.

Sweeteners that can also be used in the taste-masking coating of certainembodiments of the matrix dosage forms include glucose (corn syrup),dextrose, invert sugar, fructose, and mixtures thereof (when not used asa carrier); saccharin and its various salts, such as sodium salt;dipeptide sweeteners such as aspartame; dihydrochalcone compounds,glycyrrhizin; Steva Rebaudiana (Stevioside); chloro derivatives orsucrose such as sucralose; and sugar alcohols such as sorbitol,mannitol, xylitol, and the like. Also contemplated are hydrogenatedstarch hydrolysates and the synthetic sweeteners such as3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-1-2,2-dioxide, particularlythe potassium salt (acesulfame-K), and sodium and calcium salts thereof.The sweeteners can be used alone or in any combination thereof.

The controlled-release formulation of the present invention can furthercontain one or more pharmaceutically acceptable excipients such asgranulating aids or agents, colorants, flavorants, pH adjusters,anti-adherents, glidants and like excipients conventionally used inpharmaceutical compositions. In an embodiment, a coloring excipient canbe advantageously added as giving rise to visual change preventingabuse. It can color simultaneously the liquid or the particles or oneindependently of the other. Among suitable coloring excipients thefollowing may be cited: indigotine, cochineal carminic acid, yelloworange S, allura red AC, iron oxides, cucurmin, riboflavin, tartrazine,quinoline yellow, azorubine, amaranth, carmines, erythosine, red 2G,patented blue V, glittering blue FCF, chlorophylls, copper complexes ofchlorophylls, green S, caramel, glittering black BN, carbo medicinalisvegetabilis, brown FK and HT, carotenoids, Annatto extracts, paprikaextracts, lycopene, lutein, canthaxanthin, beetroot red, anthocyanes,calcium carbonate, titanium dioxide, aluminium, silver, gold orlitholrubin BK or any other coloring excipient suitable for an oraladministration.

In an embodiment, a sustained release formulation may be coated.Coatings may provide a variety of functions. In some embodiments,coatings may be used, for example, to achieve delayed release,resistance to acid, targeted release in the lower GI tract, avoidance ofbad taste in mouth. In some embodiments, coatings may be used to protectthe API/tablet from light and provide for better mechanical resistance.Of course it should be appreciated that a coating may serve otherfunctions as well and a person skilled in the art knows the purpose oftablet coating.

The pharmaceutical composition and/or the solid carrier particles can becoated with one or more enteric coatings, seal coatings, film coatings,barrier coatings, compress coatings, fast disintegrating coatings, orenzyme degradable coatings. Multiple coatings may be applied for desiredperformance. Further, one or more of the actives may be provided forimmediate release, pulsatile release, controlled release, extendedrelease, delayed release, targeted release, synchronized release, ortargeted delayed release. In fact, the formulation may includecombinations of typical pharmaceutical actives (e.g., pseudephedrin) andvitamins (e.g., Vitamin C), minerals (Ca, Mg, Zn, K) or othersupplements (e.g., St. John's Wort, echinacae, amino acids). Forrelease/absorption control, solid carriers can be made of variouscomponent types and levels or thicknesses of coats, with or without anactive ingredient. Such diverse solid carriers can be blended in adosage form to achieve a desired performance. The liquid formulationsmay be delivered to, and adapted for, oral, nasal, buccal, ocular,urethral, transmucosal, vaginal, topical or rectal delivery, althoughoral delivery is used mostly.

When formulated with microparticles or nanoparticles, the drug releaseprofile can easily be adapted by adding a coating, e.g., a hard or softgelatin coating, a starch coating, a resin or polymer coating and/or acellulosic coating. Although not limited to microparticles ornanoparticles (as in, e.g., microcapsules or nanocapsules), such dosageforms may be further coated with, for example, a seal coating, anenteric coating, an extended release coating, or a targeted delayedrelease coating. The term “enteric coating” as used herein relates to amixture of pharmaceutically acceptable excipients that is applied to,combined with, mixed with or otherwise added to the carrier orcomposition. The coating may be applied to an active that is compressed,molded or extruded and may also include: gelatin, and/or pellets, beads,granules or particles of the carrier or composition. The coating may beapplied through an aqueous dispersion or after dissolving in appropriatesolvent. The carrier may or may not be fully or partially biodegradable.

In an embodiment, polymethacrylate acrylic polymers can be employed ascoating polymers. In at least one embodiment, the coating is an acrylicresin lacquer used in the form of an aqueous dispersion, such as thatwhich is commercially available from Rohm Pharma under the trade nameEUDRAGIT® or from BASF under the trade name KOLLICOAT®. In a morepreferable embodiments, EUDRAGIT® E100 is used as the coating polymer,which is a cationic copolymer based on dimethylaminoethyl methacrylateand neutral methacrylic esters having a average molecular weight isapproximately 150,000. Different coating polymers of the certainembodiments can be mixed together in any desired ratio in order toultimately obtain a coating having a desirable drug dissolution profile.Coating methods can consist in spraying a solution of the polymer on thetablets, either in a pan coater or a fluid bed coating apparatus. Thesolvent may be organic or aqueous, depending on the nature of thepolymer used. In a preferable embodiment, the solvent is alcohol.Coating methods are well known in the art.

The compositions of the present invention can also be formulated asenteric coated delayed release oral dosage forms, i.e., as an oraldosage form of a pharmaceutical composition as described herein thatuses an enteric coating to effect release in the lower gastrointestinaltract. The enteric coated dosage form will generally includemicroparticles, microgranules, micropellets or microbeads of the activeingredient and/or other composition components, which are themselvescoated or uncoated. The enteric coated oral dosage form may also be acapsule (coated or uncoated) containing pellets, beads or granules ofthe solid carrier or the composition, which are themselves coated oruncoated.

Carriers for use with the present invention include permeable andsemipermeable matrices or polymers that control the releasecharacteristics of the formulation. Such polymers include, for example,cellulose acylates, acetates, and other semi-permeable polymers such asthose described in U.S. Pat. No. 4,285,987 (hereby incorporated byreference), as well as the selectively permeable polymers formed by thecoprecipitation of a polycation and a polyanion as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,142(relevant portions incorporated herein by reference).

Other carriers for use with the present invention include, e.g., starch,modified starch, and starch derivatives, gums, including but not limitedto xanthan gum, alginic acid, other alginates, benitoniite, veegum,agar, guar, locust bean gum, gum arabic, quince psyllium, flax seed,okra gum, arabinoglactin, pectin, tragacanth, scleroglucan, dextran,amylose, amylopectin, dextrin, etc., cross-linked polyvinylpyrrolidone,ion-exchange resins, such as potassium polymethacrylate, carrageenan(and derivatives), gum karaya, biosynthetic gum, etc. Other usefulpolymers include: polycarbonates (linear polyesters of carbonic acid);microporous materials (bisphenol, a microporous poly(vinylchloride),microporous polyamides, microporous modacrylic copolymers, microporousstyrene-acrylic and its copolymers); porous polysulfones, halogenatedpoly(vinylidene), polychloroethers, acetal polymers, polyesters preparedby esterification of a dicarboxylic acid or anhydride with an alkylenepolyol, poly(alkylenesulfides), phenolics, polyesters, asymmetric porouspolymers, cross-linked olefin polymers, hydrophilic microporoushomopolymers, copolymers or interpolymers having a reduced bulk density,and other similar materials, poly(urethane), cross-linked chain-extendedpoly(urethane), poly(imides), poly(benzimidazoles), collodion,regenerated proteins, semi-solid cross-linked poly(vinylpyrrolidone).

Additional additives and their levels, and selection of a primarycoating material or materials will depend on the following properties:pH levels at target site, desirability to make tablet pH dependent or pHindependent, solubility in alcohol, resistance to dissolution anddisintegration in the stomach; impermeability to gastric fluids anddrug/carrier/enzyme while in the stomach; ability to dissolve ordisintegrate rapidly at the target intestine site; physical and chemicalstability during storage; non-toxicity; easy application as a coating(substrate friendly); and economical practicality.

Further to the above, various formulations, not limiting the scope ofthe present invention, illustrating the invention are describedhereafter. A controlled-release tablet or capsule or the like comprisescolchicine as a core coated with an immediate release layer. Acontrolled-release double layer tablet or capsule or the like comprisesa layer of sustained release and a layer of immediate release. Acontrolled-release tablet with more than two layers comprises (i) one ortwo more layers of substance controlling the sustained release and (ii)one or two more layers of immediate release.

According to one embodiment of the invention, the composition comprisingcolchicine is further coated with at least one release-slowingintermediate layer of slightly soluble intermediate layer to controlrelease of colchicine.

Traditionally, colchicine immediate release dosage forms (mostlytablets, also injections or oral solutions) have been used in thetreatment of gout or FMF. Worldwide, all approved pharmaceuticalscontaining colchicine are approved only for gout and/or FMF and areimmediate release tablets. Colchicine can be used in the prevention ofcertain other inflammatory diseases such as pericarditis, PPS and, mostrecently, patients with stable coronary heart diseases. The differencebetween treatment and prevention with regard to colchicine is that intreatment, an overt disease and/or ongoing inflammation has to betreated. Thus high levels of colchicine are required, which usually goeshand in hand with unwanted side effects, most prominentlygastrointestinal insults, as well as increased risk of colchicinerelated toxicity. In prevention, one does not have to suppress ongoinginflammation but rather suppress an outbreak of inflammation. Thus,supposedly lower and steadier levels of colchicine are required and arebeneficial. As described in the present invention, this is achieved byadministering colchicine formulated as a sustained release preparation,as described above.

In the treatment of an acute inflammatory disease such as FMF or gout,high doses and high serum levels are necessary and desired to suppressinflammation. Therefore conventional tablets with a fast release and arather low plasma half-life are suitable. However, in case of preventionof a cardiovascular disease, lower levels may be sufficient to inhibitneutrophil activity. The sustained release system facilitates moresteady levels of colchicine and reduces the incidence of adverse events.

An advantage of colchicine administered as sustained release is, e.g., aflattening of the serum level curve (lower but broader peak levels)reduces the incidence of serious adverse events related to colchicinetoxicity, also in case of potential drug interactions, therebyincreasing compliance. Much of colchicine related toxicity comes fromthe fact that one or both of the excretion pathways (liver and kidney)is reduced in its activity, either by other drugs or by a disease (e.g.kidney insufficiency). In the case of a slower and extended drugabsorption (extended release), the body has also more time to excretethe colchicine from the system. In this case, it is less likely thatcolchicine levels reach toxic levels in case of defective excretion (dueto drug interaction or disease). Another potential advantage ofcolchicine administered as a sustained release formulation is thatplasma levels remain more evenly distributed (i.e., the variability ofplasma levels, such as the differences in Cmax, Tmax, AUC or otherpharmacokinetic parameters, among patients is reduced), resulting infewer “non-responders” to the treatment. In addition, administration ofcolchicine as sustained release is resistant to dose dumping, thereforethe dissolution of the composition is not significantly influenced byalcohol.

Further, sustaining the release expands the time where colchicine ispresent in the blood in therapeutic levels. This results in a moreefficient inhibition of disease progression and, thus, improving theclinical outcome.

Furthermore, for the prophylactic uses described herein, colchicine doesnot have to go deep into the tissue (like for gout), it may be active inthe blood system directly (in the vessels) where it acts on the plaquesand especially on inflammatory blood cells (neutrophils). This means,less total colchicine and lower serum levels can be therapeutic. Fastand high colchicine levels, e.g., as for treating an acute gout flarecan be avoided. Thus, lower levels of colchicine, e.g., about 0.1 toabout 0.75 mg sustained release formulations as described above (or evenless frequent doses), may be sufficient to achieve the desired clinicaloutcome.

In the normal situation, most colchicine is absorbed from the smallintestine and most passes the liver (some is also excreted in the urinevia kidney). There it is metabolized but quite a large proportion ofcolchicine goes through the liver un-metabolized. This means, it goesthrough the liver into the bile and from there it is excreted into thebig intestine (colon). There it can be resorbed into the body againwhich leads to the characteristic second peak (accounts for about 50% oftotally absorbed colchicine and is thought to be responsible forgastrointestinal problems, such as diarrhea). If colchicine isformulated as a sustained release preparation as described above, aslower release of colchicine results in a slower resorption. Thisresults in more complete metabolism of colchicine in the liver (becauseit is less busy with colchicine at a time) and, thus, less recirculationof un-metabolized colchicine. This consequently reduces the incidence ofgastrointestinal problems and increases compliance. Colchicineadministered as sustained release in accordance with the presentinvention may also be beneficial for other known side/adverse effectsassociated with colchicine treatment/administration (the skilled personis well aware of the adverse effects that may occur upon colchicineadministration or colchicine treatment). Thus, administration ofcolchicine as sustained release, as described above, results in a safetyincrease and safety benefit.

IV. Methods of Preparing a Sustained Release Formulation

The current invention additionally encompasses a method of preparingformulations of colchicine, comprising a sustained release component,and an optional immediate release component, wherein colchicine isreleased from the formulation at the sustained rate along thepre-determined or desired release profile.

In one embodiment, the colchicine compositions described in the presentinvention is in the form of a tablet. As used herein, the term “tablet”means a compressed pharmaceutical dosage form of any shape or size. Thetablets described herein may be obtained from the compositionscomprising colchicine and a pharmaceutically acceptable excipient. Anyof the colchicine compositions can be in the form of any other dosageform known in the art, specifically, any oral dosage form, for example acapsule.

In a first aspect of the invention, there is provided a controlledrelease formulation for use in oral dosage forms. The formulationincludes a mixture containing hypromellose as a hydrophilic matrix,which is effective to provide controlled release of a pharmaceuticallyactive ingredient.

Matrix systems are well known in the art. In a typical matrix system,the drug is homogenously dispersed in a polymer in association withconventional excipients. This admixture is typically compressed underpressure to produce a tablet. The API is released from the tablet bydiffusion and erosion. Matrix systems are described in detail by (i)Handbook of Pharmaceutical Controlled Release Technology, Ed. D. L.Wise, Marcel Dekker, Inc. New York, N.Y. (2000), and (ii) Treatise onControlled Drug Delivery, Fundamentals, Optimization, Applications, Ed.A. Kydonieus, Marcel Dekker, Inc. New York, N.Y. (1992), the contents ofboth of which are hereby incorporated by reference.

When the tablet is exposed to aqueous media, such as in thegastrointestinal tract, the tablet surface wets and the polymer beginsto partially hydrate forming an outer gel layer. This outer gel layerbecomes fully hydrated and begins to erode into the aqueous fluids.Water continues to permeate toward the core of the tablet permittinganother gel layer to form beneath the dissolving outer gel layer. Thesesuccessive concentric gel layers sustain uniform release of the API bydiffusion from the gel layer and exposure through tablet erosion. In thecase of the mixtures of the present invention, when included in acompressed tablet matrix, the hypromellose provides a hydrophilicswellable structure capable of functioning as the gel layer. In thisway, the drug release is controlled.

In accordance with one embodiment, the colchicine formulation of thepresent invention can be manufactured by either wet or dry granulationof a colchicine composition, blending the resulting granulate withexcipients, and then compressing the composition into tablets.

In one embodiment, wet granulation is used to prepare wet granulescomprising colchicine. A granulating liquid is used in wet granulationprocess. Both aqueous and non-aqueous liquids may be used as thegranulating liquid. In one embodiment, the granulating liquid is anaqueous liquid, or more specifically, purified or de-ionized water. Theamount of the granulating liquid used may depend on many factors, forexample, the type of the granulating liquid, the amount of thegranulating liquid used, the type of excipient used, the nature of theactive agent, and the active agent loading.

In one embodiment, the colchicine particles and suitable excipients aremixed with the granulating liquid for a sufficiently long period tofacilitate good distribution of all starting materials and good contentuniformity. Wet granulation is generally performed at temperaturesbetween about 20° C. to about 35° C., or more specifically, at roomtemperature (about 25° C.). Following wet granulation, the granulate isdried at increased temperatures to yield a dry granulate. In anembodiment, the step of drying may be performed for a sufficiently longperiod until the desired residual moisture content is reached. In anembodiment, this may be about 45° C. for about 12-48 hours. It should beappreciated that the overall time to perform the granulation process maydepend on a variety of factors, including but not limited to, thesolvents used, batch size, instruments used, etc.

Any equipment may be used to contact the granulating liquid with thecolchicine and the excipients as long as uniform distribution of thegranulating liquid is achieved. For example, small-scale production canbe achieved by mixing and wetting the colchicine and the excipients inmortars or stainless steel bowls, while for larger quantities,V-blenders with intensifier bars, planetary mixers, rotary granulators,high shear granulators, and fluid-bed granulation equipment may be used.In one embodiment, the granulator is a high shear granulator.

In one embodiment, a method of making a colchicine composition compriseswet granulating colchicine with pharmaceutically acceptable excipientsand a granulating liquid to obtain wet granules, and mixing the granulesin a next step with a second excipient to obtain a colchicinecomposition. In one embodiment, the pharmaceutically acceptableexcipient comprises a binder and a filler. In an embodiment, the bindermay be Hypromellose. In an embodiment, the filler may be lactosemonohydrate and pregelatinized starch. In another embodiment, purifiedwater is used as the granulating liquid. In an embodiment, the secondexcipient mixed with the granules may be a filler. In an embodiment, thefiller may be lactose monohydrate. The colchicine compositions cancontain about 0.1 wt % to about 10 wt %, or more specifically, about0.25 wt % to about 0.75 wt %, of colchicine, based on the total weightof the colchicine composition.

In an embodiment, the method of making a composition comprises wetgranulating colchicine with a pharmaceutically acceptable excipient toobtain wet granules, and mixing the granules with a filler to obtain acolchicine composition. In some embodiments, the method further includesdrying the mixture. In another embodiment, the wet granules are dried toobtain dried granules, and then the dried granules are mixed with abinder, a filler, or both to obtain the composition. In anotherembodiment, the dried granules can be milled to obtain milled granulesbefore mixing the milled dried granules with the binder, a filler, orboth. The method can further include mixing the colchicine compositionwith a glidant, a lubricant, or both to obtain a blend or compressingthe blend to obtain a tablet. In one embodiment, the glidant may beTalc. In another embodiment, the lubricant may be Stearic acid. Themethod can further include coating the tablet.

In another embodiment, a method of making a colchicine tablet compriseswet granulating colchicine with a pharmaceutically acceptable excipientto obtain wet granules; drying the wet granules to obtain driedgranules; milling the dried granules to obtain milled granules; mixingthe milled granules with a filler to obtain the composition; mixing thecomposition with a glidant, a lubricant, or both to obtain a blend; andcompressing the blend to obtain a colchicine tablet of the presentinvention.

In some embodiments, the wet granules are dried to obtain dried granulesbefore mixing with a second excipient, for example a filler. Wetgranules can be dried by any suitable means to remove the granulatingliquid and to form dried granules containing colchicine and thepharmaceutically acceptable excipient. The conditions and duration ofdrying depend on factors such as the liquid used and the weight of thegranulating particles. Examples of suitable drying methods include, butare not limited to, tray drying, forced air drying, microwave drying,vacuum drying and fluid bed drying.

After drying, dried granules may be mixed directly with an excipient,for example, a filler, a binder, or a lubricant, for further processing.Alternatively, dried granules may optionally be subjected to additionalprocessing steps prior to mixing with the excipient. For example, driedgranules may be sized to reduce particle size prior to mixing with anexcipient. Exemplary sizing operations include milling or sieving. Anysuitable equipment for reducing the particle size may be used in thepresent invention.

Suitable excipients may be added extragranularly and mixed with thegranules to form colchicine compositions. As used herein, the term“extragranular” or “extragranularly” means that the referenced material,for example, a suitable excipient, is added or has been added as a drycomponent after wet granulation. In one embodiment, a filler, a binder,a glidant and a lubricant are added extragranularly to the granules andmixed to form a blend. The blend may be encapsulated directly intocapsule shells, for example, hard gelatin shells, to form capsuleformulations. Alternatively, the blend may be compressed into tablets.In some embodiments, the granules are dried granules or milled, driedgranules.

Mixing can be carried out for a sufficient time to produce homogeneousmixtures or blends. Mixing may be accomplished by blending, stiffing,shaking, tumbling, rolling, or by any other method to achieve ahomogeneous blend. In some embodiments, the components to be mixed arecombined under low shear conditions in a suitable apparatus, such as aV-blender, tote blender, double cone blender or any other apparatuscapable of functioning under low shear conditions.

The homogenous mixtures or blends are then compressed using any methodsuitable in the industry. The mechanical force will define the physicalproperties of the tablets, especially the crushing strength of theresulting tablet. The mechanical strength interacts with the initialswelling of the tablet and dilution speed of the tablet core. Thiseffect is well known in the art and can be adjusted and controlledduring the lifecycle of the product. For the colchicinesustained-release formulation of the present invention, the compressionstrengths used may range from about 30 N to about 130 N. In oneembodiment, the compression strength may be about 100 N. In anotherembodiment, the compression strength may be about 100 N+/−15 N.

The colchicine tablets prepared from the above described methods exhibitacceptable physical characteristics including good friability andhardness. As per EP and USP guidelines, the colchicine tablets disclosedherein have friability in the range of about 0% to less than about 1%.

The colchicine tablet can be coated. Coating the tablet may be performedby any known process. A coating for the colchicine tablet disclosedherein can be any suitable coating, such as, for example, a functionalor a non-functional coating, or multiple functional or non-functionalcoatings. By “functional coating” is meant to include a coating thatmodifies the release properties of the total formulation, for example, asustained-release coating. By “non-functional coating” is meant toinclude a coating that is not a functional coating, for example, acosmetic coating. A non-functional coating can have some impact on therelease of the active agent due to the initial dissolution, hydration,perforation of the coating, etc., but would not be considered to be asignificant deviation from the non-coated composition.

In one embodiment, a colchicine composition comprises colchicine, abinder, a filler, a retarding agent, a glidant, and a lubricant. In anembodiment, a colchicine composition comprises about 0.25 to about 0.75mg colchicine; about 10 to about 80 mg lactose monohydrate; about 5 toabout 50 mg pregelatinized starch; about 1 to about 30 mg Hypromellose 6mPa*s; about 5 to about 40 mg Retalac (compound of lactose monohydrateand Hypromellose 4000 mPa*s 50/50 w/w %); about 0.5 to about 5 mg Talc;and about 0.5 to about 5 mg Stearic acid 50. In an embodiment, thecolchicine composition comprises about 0.5 mg colchicine, about 59 mglactose monohydrate; about 7.5 mg pregelatinized starch; about 1 mgHypromellose 6 mPa*s; about 30 mg Retalac (compound of lactosemonohydrate and Hypromellose 4000 mPa*s 50/50 w/w %); about 1 mg Talc;and about 1 mg Stearic acid 50. The colchicine dosage form has a totalweight of about 100 mg. The colchicine composition can be in the form ofa tablet.

V. Treatment Methods Using Sustained Release Colchicine

The present invention also presents a method of treatment or preventionof cardiovascular diseases and/or inflammatory disorders in a subject,comprising administering to the subject a therapeutically effectiveamount of a colchicine formulation of the present invention, whereincolchicine is released from the formulation at a sustained rate along apre-determined or desired release profile. The method of the currentinvention possesses the flexibility to selectively adjust thepharmacokinetics of the administered formulations depending on thenature of the condition and needs of the patients due to the noveldesign of the colchicine formulation that comprises an extended releasecomponent and an optional immediate release component, and the releaseprofiles of both components can be selectively modified during thepreparation process as described above to comply with the predeterminedrelease profile.

In one embodiment, treatment includes the application or administrationof a colchicine formulation as described herein to a patient, where thepatient has, or has the risk of developing a cardiovascular diseaseand/or an inflammatory disorder. In another embodiment, treatment isalso intended to include the application or administration of apharmaceutical composition comprising the colchicine formulation, to apatient, where the patient has, or has the risk of developing acardiovascular disease and/or inflammatory disorder.

As used herein, the term “cardiovascular disease” refers to any diseaseinvolving the heart and/or the vascular system (all blood vessels incl.arteries, capillaries and veins). This includes all diseases listed inchapter IX “Diseases of the circulatory system (I00-I99)” of theInternational Statistical Classification of Diseases and Related HealthProblems 10th Revision (ICD-10) Version for 2010, by the World HealthOrganisation.

More specifically, all diseases of this ICD-10 class which involve a)inflammation of any part of the heart or blood vessel as well as b)ischemia/atherosclerosis/thickening of any blood vessel of thecirculatory system.

Colchicine as described herein is for use in the treatment and/orprevention of any inflammatory disorder involving the heart tissueselected from ICD-10 sections 100-199. More specifically, these includeacute and recurrent pericarditis as well as post-surgical complicationsinvolving inflammation of the pericardium (Postcardiotomy syndrome,Postpericardiotomy syndrome, pericardial effusion). Other inflammatoryheart diseases covered are any form of myocarditis, endocarditis andarterial fibrillation.

The proposed mechanism of action in this indication is the inhibition ofplaque instability by neutrophil inhibition. In stable coronary disease,fatty materials accumulate at the blood vessel and form a stable plaque.This plaque may become subject to attack by neutrophils. This may causeplaque instability and consequently leads to plaque rupture and clinicalevents. Therefore, colchicine as described herein is for use intreatment and/or prevention of any disease of the cardiovascular systemwhich involves ischemia, atherosclerosis and/or thickening of bloodvessels (arteries, capillaries, veins) due to plaque formation with arisk of clinical events due to plaque instability. Claimed are alldiseases classified in ICD-10 section 100-199 fulfilling any of theserequirements. Examples are stable coronary disease, cardiovascularatherosclerosis, and atherosclerosis of the peripheral vascular system,Abdominal Aortic Aneurysm (AAA) and carotid and iliofemoral/renalatheromas (e.g. 125, 170).

In the context of the present invention, an acute cardiovascular eventin a patient with stable cardiovascular disease is preferably acardiovascular event in a patient with stable coronary disease. In thecontext of the present invention, the term “stable coronary disease” and“stable coronary heart disease” have the same meaning and are usedinterchangeable. Both terms include the medical condition stablecoronary artery disease (SCAD). “Stable” in the context of the terms“stable cardiovascular disease”, “stable coronary disease” or “stablecoronary heart disease” is defined as any conditions of diagnosedcardiovascular disease in the absence of acute cardiovascular events.Hence, e.g. stable coronary disease defines the different evolutionaryphases of coronary disease, excluding the situations in, which coronaryartery thrombosis dominates clinical presentation (acute coronarysyndrome).

Colchicine in the context of the present invention can be used for theprevention and/or treatment of cardiovascular diseases. Cardiovasculardiseases include, but are not limited to, heart diseases as described,e.g., in Robbins and Cotran, Pathologic Basis of Disease, EighthEdition, Saunders Elsevier. Cardiovascular disease refers to a group ofdiseases of the circulatory system including the heart, blood andlymphatic vessels. In particular, cardiovascular disease may includevascular diseases involving atherosclerosis, plaque formation ordisposition. The most common cardiovascular diseases are coronary heartdisease and stroke. Non-limiting examples of cardiovascular diseasewhich may be prevented or treated according to the methods of theinvention include coronary heart disease (disease of the blood vesselssupplying the heart muscle), cerebrovascular disease (disease of theblood vessels supplying the brain), peripheral arterial disease (diseaseof blood vessels supplying the arms and legs), rheumatic heart disease(damage to the heart muscle and heart valves from rheumatic fever,caused by streptococcal bacteria), congenital heart disease(malformations of heart structure existing at birth), deep veinthrombosis and pulmonary embolism (blood clots in the leg veins, whichcan dislodge and move to the heart and lungs), hyperlipemia (anexcessive level of blood fats, such as LDL), high blood pressure,coronary artery disease, atherosclerosis, ischemic diseases, abdominalaortic aneurysm, carotid and iliofemoral/renal atheromas, heart failure,cardiac rhythm defects, arteriosclerosis, heart attack and stroke. Heartattacks and strokes are usually acute events and are mainly caused by ablockage that prevents blood from flowing to the heart or brain. Themost common reason for this is a build-up of fatty deposits on the innerwalls of the blood vessels that supply the heart or brain. Strokes canalso be caused by bleeding from a blood vessel in the brain or fromblood clots.

Especially, in the context of the present invention, colchicine can beused for the prevention of acute pericarditis, recurrent pericarditis,recurrent pericarditis in patients with a history of pericarditis,post-pericardiotomy syndrome (PPS), PPS in patients undergoing cardiacsurgery, and cardiovascular events in patients with stable coronary(heart) disease (the cardiovascular events can be acute cardiovascularevents). In some embodiments, colchicine according to the presentinvention is not used to treat acute pericarditis. In other embodiments,colchicine according to the present invention is not used to treatrecurrent pericarditis.

Pericarditis is an inflammatory disease involving the pericardium, athin double-walled fibroelastic sac, surrounding the heart. Due toinflammation, it comes to irritation and swelling of the pericardium.This causes the sac to rub against the heart which causes chest pain,the most common symptom of pericarditis. Pericarditis is the most commonform if inflammatory disorder of the heart, though very rare on apopulation basis. Pericarditis is very heterogeneous in its origin,clinical manifestations and duration of symptoms. It can either occur asisolated clinical problem or as a manifestation of a systemic disease.In most cases (90%), pericarditis is of idiopathic (spontaneous,unknown) etiology but may also occur secondary to systemic infections,acute myocardial infarction or autoimmune diseases. Thepost-pericardiotomy syndrome (PPS) may be a troublesome complicationfollowing cardiac surgery occurring a few days to several weeks afterthe surgical operation. The estimated incidence of the syndrome has arelatively wide range affecting from 10 to 40% of patients submitted tocardiac surgery (Prince and Cunhe, 1997, Heart Lung, 26:165).

Non-limiting examples of (acute) cardiovascular events are injury of theatherosclerotic wall, acute coronary syndrome, out-of-hospital cardiacarrest, or noncardioembolic ischemic stroke. Further such events aredescribed, e.g., in Robbins and Cotran, Pathologic Basis of Disease,Eighth Edition, Saunders Elsevier.

In an embodiment, the colchicine formulation of the present inventionmay be used to treat inflammatory disease other than those mentionedabove. In an embodiment, the inflammatory disease includes, but is notlimited to, gout, familial Mediterranean fever, Behçet's disease,Age-related macular degeneration and Alzheimer's disease.

Patients/subjects which suffer from the above described disease and/orwhich are suitable for treatment with colchicine according to thepresent invention can be diagnosed by conventional and/or routineprocedures. The skilled person is well aware of them. Diagnosis is alsodescribed, e.g., in Robbins and Cotran, Pathologic Basis of Disease,Eighth Edition, Saunders Elsevier.

In an embodiment, the colchicine formulation as described herein isuseful for the treatment of various cardiovascular diseases and/orinflammatory disorders. In some embodiments, treatment of acardiovascular disease and/or an inflammatory disorder is intended toinclude remediation of, improvement of, amelioration of, lessening ofthe severity of, or reduction in the time course of, a disease, disorderor condition, or any parameter or symptom thereof. In an embodiment ofthe present invention, the term “disorder”, “disease”, or “condition” isto be understood as cardiovascular disease and/or inflammatory disorderas described above. In the context of the present invention,“amelioration” refers, without limitation, to any observable beneficialeffect.

In accordance with the present invention, the colchicine formulationherein can be used to promote a positive therapeutic response withrespect to the cardiovascular disease and/or inflammatory disorder. A“positive therapeutic response” with respect to the cardiovasculardisease and/or inflammatory disorder is intended to include animprovement in the disease can be evidenced by, for example, a delayedonset of clinical symptoms of the disease or condition, a reduction inseverity of some or all clinical symptoms of the disease or condition, aslower progression of the disease or condition, an improvement in theoverall health or well-being of the subject, or by other parameters wellknown in the art that are specific to the particular disease.

In another embodiment, the colchicine formulation as described herein isuseful in the prevention of various cardiovascular diseases and/orinflammatory disorders. In the context of the present invention, theterm “prevention” is well known in the art. For example, apatient/subject suspected of being prone to suffer from a disorder ordisease as defined herein may, in particular, benefit from a preventionof the disorder or disease. The subject/patient may have asusceptibility or predisposition for a disorder or disease, includingbut not limited to hereditary predisposition. Such a predisposition canbe determined by standard assays, using, for example, genetic markers orphenotypic indicators. It is to be understood that a disorder or diseaseto be prevented in accordance with the present invention has not beendiagnosed or cannot be diagnosed in the patient/subject (for example,the patient/subject does not show any clinical or pathologicalsymptoms). Thus, the term “prevention” comprises the use of compounds ofthe present invention before any clinical and/or pathological symptomsare diagnosed or determined or can be diagnosed or determined by theattending physician. Prevention includes, without limitation, to avoidthe disease or condition from occurring in patient and/or subject thatmay be predisposed to the disease but does not yet experience or exhibitsymptoms of the disease (prophylactic treatment).

Colchicine according to the present invention may also be used incombination with conventional therapy for any of the diseases disclosedherein. Such conventional therapies are well known in the art and theskilled person knows any such therapies. Colchicine as described hereinmay also be used in combination with colchicine-compatible statins. Ingeneral, non-limiting examples of statins are atorvastatin (Lipitor®,Torvast®), fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®,Altoprev®), pitavastatin (Livalo®, Pitava®), pravastatin (Pravachol®,Selektine®, Lipostat®), rosuvastatin (Crestor®) and simvastatin (Zocor®,Lipex®). In connection with the present invention, colchicine-compatiblestatins are used. Preferably, in the context of the present invention,the combination of the composition of the present invention with thecolchicine-compatible statins are accomplished in connection with stablecoronary heart disease. Such statins preferably are statins which, dueto the nature of their mechanism of action, metabolism and/or clearancedo not, or only to a small extent, interfere with the mechanism ofaction, metabolism and/or clearance of colchicine and therefore show areduced risk, severity and/or incidence of drug-related drug adverseevents when given in combination with colchicine.

In an embodiment, the use of colchicine is in fixed (within the samepharmaceutical preparation) or unfixed (different pharmaceuticalpreparation) combination. “Fixed combination” is to be understood asmeaning a combination whose active ingredients are combined at fixeddoses in the same vehicle (single formula) that delivers them togetherto the point of application. Fixed combination can mean, e.g., in asingle tablet, solution, cream, capsule, gel, ointment, salve, patch,suppository or transdermal delivery system. “Unfixed combination” asused herein is to be understood as meaning that the activeingredients/components are in more than one vehicle (e.g. tablets,solutions, creams, capsules, gels, ointments, salves, patches,suppositories or transdermal delivery systems). Each of the vehicles cancontain a desired pharmaceutical composition or active component. Forexample, a preferred unfixed combination as described herein means thatone vehicle contains colchicine, as described herein, and anothervehicle contains a colchicine-compatible statin, as described herein.Examples of colchicine as described herein in fixed or unfixedcombination(s) encompass(es) colchicine in combination with one or morecolchicine-compatible statins selected from the group consisting ofatorvastatin, rosuvastatin, simvastatin and pravastatin. Specifically,colchicine as described herein in fixed or unfixed combination is to beunderstood as meaning colchicine in combination with atorvastatin.Specifically, colchicine as described herein in fixed or unfixedcombination is to be understood as meaning colchicine in combinationwith rosuvastatin. Specifically, colchicine as described herein in fixedor unfixed combination is to be understood as meaning colchicine incombination with simvastatin. Specifically, colchicine as describedherein in fixed or unfixed combination is to be understood as meaningcolchicine in combination with pravastatin.

In some embodiments, colchicine as described herein may be used incombination with a statin and another agent, such asezetimibe/simvastatin. Colchicine as described herein may be used incombination with other drugs, e.g, which are used in medicine and areknown to the skilled person (e.g. antibiotics, NSAID (non-steroidalanti-inflammatory drugs), corticosteroids).

VI. Administration Methods

Methods of preparing and administering the colchicine formulation of thepresent invention to a subject in need thereof are well known to or arereadily determined by those skilled in the art. The route ofadministration of the colchicine formulation can be, for example, oral,parenteral, by inhalation or topical. The term parenteral as used hereinincludes, e.g., intravenous, intraarterial, intraperitoneal,intramuscular, subcutaneous, rectal, or vaginal administration.

Colchicine when used as a composition in the context of the presentinvention may include one or more pharmaceutically acceptable carriersand thus may be prepared in the form of a local formulation, in orderfor it to be administered. The pharmaceutically acceptable carrier mayinclude saline, sterile water, linger liquid, buffer saline, a dextrosesolution, a malto dextrin solution, glycerol, ethanol and mixtures ofone or more thereof, and also may include an additive such as anantioxidant, a buffer, a bacteriostatic agent or the like, as necessary.Furthermore, a diluent, a dispersant, a surfactant, a binder and alubricant may be added when the composition according to the presentinvention is prepared, e.g., in the form of a local formulation such asan ointment, lotion, cream, gel, skin emulsion, skin suspension, patchor spray.

Non-limiting examples for administration of the compound and orcompositions according to the present invention include coated anduncoated tablets, soft gelatine capsules, hard gelatine capsules,lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs,powders and granules for reconstitution, dispersible powders andgranules, medicated gums, chewing tablets and effervescent tablets. Thecomposition according to the present invention can administered in anypharmaceutical form for oral (e.g. solid, semi-solid, liquid), dermal(e.g. dermal patch), sublingual, parenteral (e.g. injection), ophthalmic(e.g. eye drops, gel or ointment) or rectal (e.g. suppository)administration. In an embodiment, the composition is formulated as atablet, capsule, suppository, dermal patch or sublingual formulation.

The pharmaceutical compositions used in this invention comprisepharmaceutically acceptable carriers, including, e.g., ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol, andwool fat.

Certain pharmaceutical compositions used in this invention can be orallyadministered in an acceptable dosage form including, e.g., capsules,tablets, aqueous suspensions or solutions. Certain pharmaceuticalcompositions also can be administered by nasal aerosol or inhalation.Such compositions can be prepared as solutions in saline, employingbenzyl alcohol or other suitable preservatives, absorption promoters toenhance bioavailability, and/or other conventional solubilizing ordispersing agents.

The amount of the colchicine formulation to be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. The compositioncan be administered as a single dose, multiple doses or over anestablished period of time in an infusion. Dosage regimens also can beadjusted to provide the optimum desired response (e.g., a therapeutic orprophylactic response).

In some situations, the composition of the present invention can beparenterally administered. Preparations for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, andemulsions. Examples of non-aqueous solvents are propylene glycol,polyethylene glycol, vegetable oils such as olive oil, and injectableorganic esters such as ethyl oleate. Aqueous carriers include, e.g.,water, alcoholic/aqueous solutions, emulsions or suspensions, includingsaline and buffered media. In the subject invention, pharmaceuticallyacceptable carriers include, but are not limited to, 0.01-0.1 M andpreferably 0.05 M phosphate buffer or 0.8% saline. Other commonparenteral vehicles include sodium phosphate solutions, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's, or fixedoils. Intravenous vehicles include fluid and nutrient replenishers,electrolyte replenishers, such as those based on Ringer's dextrose, andthe like. Preservatives and other additives may also be present such as,for example, antimicrobials, antioxidants, chelating agents, and inertgases and the like.

Parenteral formulations can be a single bolus dose, an infusion or aloading bolus dose followed with a maintenance dose. These compositionscan be administered at specific fixed or variable intervals, e.g., oncea day, or on an “as needed” basis.

The composition according to the present invention may be administeredin a dose range varying depending on the patient's body weight, age,gender, health condition, diet, administration time, administrationmethod, excretion rate and disease severity. The compounds of thepresent invention as compounds per se in their use as pharmacophores oras pharmaceutical compositions can be administered to the patient and/orsubject at a suitable dose. The dosage regiment will be determined bythe attending physician and clinical factors. As is well known in themedical arts, dosages for any one patient depends upon many factors,including the patient's size, body surface area, age, the particularcompound to be administered, sex, time and route of administration,general health, and other drugs being administered concurrently.Generally, the regimen as a regular administration of the pharmaceuticalcomposition comprising the herein defined should be, e.g., in a range asdescribed below. Progress can be monitored by periodic assessment.

The composition according to the present invention can be administeredwith a single dose or with 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses, ifdesired. The composition can be administered 1, 2, 3, 4, 5, 6, 7, 8, 9or 10 times per day. Preferably, colchicine according to the presentinvention is administered once per day. More preferably, colchicineaccording to the present invention is administered once per day as asingle dose.

The composition according to the present invention can be administeredregularly for long periods of time. In an embodiment, the compositioncan be administered regularly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or moreyears. In another embodiment, the composition can be administeredregularly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months. Inother embodiments, the composition can be administered regularly for 1,2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks. As used herein, the term“regularly” refers to administration of the composition at regular timesor intervals over a period of time. For instance, the composition may beadministered to a patient once daily for three years. In otherembodiments, the composition may be administered to a patient once everyother day for 5 years. It should be appreciated that the frequency ofadministration may vary based on a number of factors, including, but notlimited to, the severity of disease, the overall health of the patient,any additional medications the patient is taking, and whether thetreatment is prophylactic or not. It should also be appreciated that thefrequency of administration may be adjusted at any point.

The amount/concentration/dose of the composition according to thepresent invention can be between 0.1 mg and 5.0 mg, 0.1 mg and 2.0 mg,0.1 mg to 1.5 mg, 0.1 mg to 1.0 mg, 0.1 mg to 0.75 mg, 0.1 mg to 0.5 mg,0.25 mg to 5.0 mg, 0.25 mg to 2.0 mg, 0.25 mg to 1.5 mg, 0.25 mg to 1.0mg, 0.25 mg to 0.75 mg or 0.25 mg to 0.5 mg. In an embodiment, thecomposition according to the present invention is administered at adaily dose of colchicine of between about 0.1 mg and about 0.75 mg orbetween about 0.1 mg and about 0.5 mg. In another embodiment, thecomposition according to the present invention is administered at adaily dose of colchicine of between about 0.25 mg to about 0.75 mg orbetween about 0.25 mg to about 0.5 mg. In an embodiment, the compositionaccording to the present invention is administered at a daily dose ofabout 0.5 mg colchicine.

In a preferred embodiment, the amount/concentration of colchicine asused herein can be administered at the first day of administration in ahigher dose (concentration/amount) compared to the administration ofcolchicine at the following days(s) of administration (maintenanceadministration/maintenance dose of administration). Alternatively suchdecreased dose (maintenance dose) can be started after 2, 3, 4, 5, 6, 7,8, 9 or 10 days of initial administration of the higher dose. In casethe course of treatment is any such as described above, the higherdose/amount/concentration of colchicine (e.g. at the first day ofadministration) can be any as described above, provided that themaintenance dose (the dose/amount/concentration of colchicine at thedays following the higher dose/amount/concentration) is lower than theinitial dose/amount/concentration of colchicine (e.g. at the first dayof administration). Preferably, the composition of the invention isadministered with a dose of colchicine of between about 1.0 mg to about2.0 mg at the first day (preferably as a single dose) of administrationand the maintenance dose of colchicine at the following day(s) ofadministration is between about 0.5 mg to about 1.0 mg.

In keeping with the scope of the present disclosure, the colchicineformulation of the present invention can be administered to a human orother animal in accordance with the aforementioned methods of treatmentin an amount sufficient to produce a therapeutic effect. The colchicineformulation can be administered to such human or other animal in aconventional dosage form prepared by combining the colchicineformulation of the invention with a conventional pharmaceuticallyacceptable carrier or diluent according to known techniques. It will berecognized by one of skill in the art that the form and character of thepharmaceutically acceptable carrier or diluent is dictated by the amountof active ingredient with which it is to be combined, the route ofadministration and other well-known variables.

By “therapeutically effective dose or amount” or “effective amount” isintended an amount of the colchicine formulation that when administeredbrings about a positive therapeutic response with respect to treatmentof a patient with a disease to be treated, e.g., an improvement in thedisease can be evidenced by, for example, a delayed onset of clinicalsymptoms of the disease or condition, a reduction in severity of some orall clinical symptoms of the disease or condition, a slower progressionof the disease or condition, an improvement in the overall health orwell-being of the subject, or by other parameters well known in the artthat are specific to the particular disease.

The invention also provides for the use of the colchicine formulation inthe manufacture of a medicament for treating a subject for treating acardiovascular disease and/or inflammatory disorder, wherein themedicament is used in a subject that has been pretreated or isconcurrently being treated with at least one other therapy, By“pretreated” or “pretreatment” is intended the subject has received oneor more other therapies prior to receiving the medicament comprising thecolchicine formulation. “Pretreated” or “pretreatment” includes subjectsthat have been treated with at least one other therapy within 2 years,within 18 months, within 1 year, within 6 months, within 2 months,within 6 weeks, within 1 month, within 4 weeks, within 3 weeks, within 2weeks, within 1 week, within 6 days, within 5 days, within 4 days,within 3 days, within 2 days, or even within 1 day prior to initiationof treatment with the medicament comprising the colchicine formulation.By “concurrent” or “concomitant” is intended the subject is receivingone or more other therapies while at the same time receiving themedicament comprising the colchicine formulation. It is not necessarythat the subject was a responder to pretreatment with the prior therapyor therapies or a responder to the concurrent therapy or therapies.Thus, the subject that receives the medicament comprising the colchicineformulation could have responded, or could have failed to respond, topretreatment with the prior therapy, or to one or more of the priortherapies where pretreatment comprised multiple therapies.

All of the references cited above, as well as all references citedherein, are incorporated herein by reference in their entireties.

While the invention has been illustrated and described in detail inabove, such illustration and description are to be consideredillustrative or exemplary and not restrictive. It will be understoodthat changes and modifications may be made by those of ordinary skillwithin the scope and spirit of the following claims. In particular, thepresent invention covers further embodiments with any combination offeatures from different embodiments described above and below.

The present invention is additionally described by way of the followingillustrative non-limiting examples that provide a better understandingof the present invention and of its many advantages. The followingexamples are included to demonstrate preferred embodiments of theinvention. It should be appreciated by those of skill in the art thatthe techniques disclosed in the examples which follow representtechniques used in the present invention to function well in thepractice of the invention, and thus can be considered to constitutepreferred modes for its practice. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments which are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention.

EXAMPLES Example 1 Colchicine Sustained Release Tablet

This example illustrates a colchicine sustained release tablet. Thetablet uses the ingredients and concentrations shown in Table 1 below.

mg/ Ingredient Tablet Tablet % Function Colchicine 0.500 0.5 ActivePharmaceutical Ingredient (API) Lactose monohydrate 59.00 59.0 FillingAgent Pregelatinized Starch 7.50 7.5 Filling Agent Hypromellose 1.0001.0 Binder 6 mPa * s Purified water¹ q.s. q.s. Diluent for API andBinder Lactose monohydrate 10.00 10.00 Filling Agent Retalac (Compoundof 20.00 20.00 Retarding Agent Lactose monohydrate and Hypromellose 4000mPa * s 50/50 w/w %) Talc 1.00 1.0 Glidant Stearic acid 50 1.00 1.0Lubricant Total tablet weight 100.00 ¹removed within the [mg]: process

The concentrations may be altered to change certain properties of theformulations, for instance, the dissolution profile. Table 2 shows theranges for each ingredient.

Ingredient Range Function Colchicine 0.5-0.75 Active PharmaceuticalIngredient (API) Lactose monohydrate 10-80  Filling Agent PregelatinizedStarch 5-50 Filling Agent Hypromellose 6 mPa * s 1-30 Binder Purifiedwater¹ q.s. Diluent for API and Binder Lactose monohydrate 10-30 Filling Agent Retalac (Compound of 5-40 Retarding Agent Lactosemonohydrate and Hypromellose 4000 mPa * s 50/50 w/w %) Talc 0.5-5  Glidant Stearic acid 50 0.5-5   Lubricant Total tablet weight ¹removedwithin the process [mg]:

Example 2 Method of Making a Colchicine Sustained Release Tablet

The above ingredients are utilized to make a tablet to the followingworking directions:

Granulation:

The granulation was performed in a Kenwood mixer. The colchicine andhypromellose 6 Mpa*s were first weighed and separately dissolved intopurified water. This solution of hypromellose 6 Mpa*s was filled in themixer containing the lactose within 1.5 min followed by a 3 minutemixing time. Subsequently, the dissolved colchicine was sprayed with afiling agent (e.g., lactose monohydrate) under continuous mixing over aperiod of 15 minutes. These steps were performed at room temperature.The wet granulate was then passed through a 1.0 mm hand sieve. It wasthen dried in an oven (Haeraeus) at 45° C. for 26 h to a residualmoisture content of 0.53%, and passed through a 0.8 mm sieve shaker(Erweka AR 400). Density parameters were tested (Engelmann). Bulkdensity 0.53 g/ml, compacted bulk density 0.67 g/ml, Hausner ratio 1.26.Rheology: Flow time 4 sec; Slope angle 23.8°.

Blending:

Following the granulation process, the granulate is compounded with afilling agent (e.g., lactose monohydrate), a retarding agent (e.g.,Retalac), and other excipients (e.g., flow enhancer, glidants and/orlubricants) to support the tablet compression process. To this end,these ingredients were placed manually through a 0.8 mm sieve and mixedwith the granulate in a cube mixer (Erweka) for 10 minutes. In oneembodiment, the glidant used may be Talc. In another embodiment, thelubricants used may be Stearic acid. The granulate will then be blendedusing a suitable mixer.

Compression of Tablets:

To form the tablets, a compression force is needed. The mechanical forcewill define the physical properties of the tablets, especially thecrushing strength of the resulting tablet. The mechanical strengthinteracts with the initial swelling of the tablet and dilution speed ofthe tablet core. This effect is well known in the art and can beadjusted and controlled during the lifecycle of the product.

Tableting was performed on a Korsch (EK 0) tablet press with a roundtabletting tool, biconvex, 6 mm in diameter. Average tablet hardness wasapproximately 100 N+/−15 N. Tablets measured about 100 mg in mass,friability was not measurable. Breaking strength and hardness weremeasured with a Erweka Multickeck. Friability was measured with a ErwekaFriabilator and a Mettler analytical balance. The dimensions weremeasured using a Mitutoyo caliper.

Example 3 Measurements of Dissolution Profiles of Sustained-ReleaseColchicine Formulations

The dissolution of the sustained release formulation of colchicine wasmeasured at various time points. The compositions were dissolved in 500ml of water at 37° C. and stirred continuously over a period of 6 hours.Samples were drawn at several time points to study the kinetics of thedissolution process of the drug substance within the hydrophilic matrixsystem. Colchicine content in the samples was analyzed using HPLCanalysis.

Several batches were tested to determine the optimal dissolution profilefor the sustained release formulation. The release can be modified byboth the concentration of hypromellose or by using different viscositygrades of hypromellose (e.g. 1000 mPa or 10000 mPa). In the batchestested below, the viscosity grade remained constant, however, theconcentration of hypromellose 4000 mPa in the tablet was modified.

Table 3 below summarizes the various compositions that were tested.

Mass per Per batch Material name Mass [%] Tbl. [mg] [g] −0.5% +0.5% Stemgranulate: (common for 3 Tablet mixings) PE Colchicine 0.500 0.500 7.507.46 7.54 Lactose monohydrate EP 59.000 59.000 885.00 880.6 889.4Pregelatinized Starch USP 7.500 7.500 112.50 111.94 113.06 FBHypromellose 6 mPa*s 1.000 1.000 15.00 14.93 15.08 EP/JP/USP Waterpurified * for 0.000 4.000 60.00 59.70 60.30 Colchicine Water purified *0.000 8.300 124.50 123.88 125.1 For Hypromellose Batch 1: Tableting mix10% Retalac (compression strength = 100N): Lactose monohydrate EP 20.00020.000 80.0 79.6 80.4 (Filling agent ad 100 mg per tablet) PE Retalac(50% Lactose/ 10.000 10.000 40.00 39.8 40.2 50% Hypromellose 4000 mPas)Talc EP/JP 1.000 1.000 4.00 3.98 4.02 Stearic acid 50 EP 1.000 1.0004.00 3.98 4.02 Total tablet weight: 100.000 100.000 Batch 2: Tabletingmix 15% Retalac (compression strength = 100N): Lactose monohydrate EP15.000 15.000 60.00 59.7 60.3 (Filling agent ad 100 mg per tablet) PERetalac (50% Lactose/ 15.000 15.000 60.00 59.7 60.3 50% Hypromellose4000 mPas) Talc EP/JP 1.000 1.000 4.00 3.98 4.02 Stearic acid 50 EP1.000 1.000 4.00 3.98 4.02 Total tablet weight: 100.000 100.000 Batch 3:Tableting mix 20% Retalac (compression strength = 100N): Lactosemonohydrate EP 10.000 10.000 40.00 79.6 80.4 (Filling agent ad 100 mgper tablet) PE Retalac (50% Lactose/ 20.000 20.000 80.00 79.6 80.4 50%Hypromellose 4000 mPas) Talc EP/JP 1.000 1.000 4.00 3.98 4.02 Stearicacid 50 EP 1.000 1.000 4.00 3.98 4.02 Total tablet weight: 100.000100.000 Batch 4: Tableting mix 30% Retalac (compression strength = 50Nand 130N): Lactose monohydrate EP 0.000 0.000 00.00 0.0 0.0 (Fillingagent ad 100 mg per tablet) PE Retalac (50% Lactose/ 30.000 30.000120.00 119.40 120.60 50% Hypromellose 4000 mPas) Talc EP/JP 1.000 1.0004.00 3.98 4.02 Stearic acid 50 EP 1.000 1.000 4.00 3.98 4.02 Totaltablet weight: 100.000 100.000 Batch 5: Tableting mix 0% Retalac(compression strength = 100N): Lactose monohydrate EP 30.000 30.000120.00 119.40 120.60 (Filling agent ad 100 mg per tablet) PE Retalac(50% Lactose/ 0.000 00.000 00.00 0.0 0.0 50% Hypromellose 4000 mPas)Talc EP/JP 1.000 1.000 4.00 3.98 4.02 Stearic acid 50 EP 1.000 1.0004.00 3.98 4.02 Total tablet weight: 100.000 100.000

The dissolution profiles of the various batches are provided in Tables4-6 and FIGS. 1-4. In particular, the dissolution profile for Batches1-3 is summarized in Table 4 and FIG. 1. The profile for Batch 1 showsapproximately a 92% release within about 30 minutes, followed by aconstant release. Complete dissolution occurred after 2 hours. Batch 2shows approximately a 83% release within about 30 minutes, followed by aconstant release. Complete dissolution occurred after 2 hours. Batch 3shows approximately a 74% release within about 30 minutes, followed by aconstant release. Complete dissolution occurred after 2 hours.

TABLE 4 Concentration Hour Hour Hour Hour Hour Retardant Sample 0 0.5 12 4 10% Retalac 1. 90.6 98.1 99.1 98.9 2. 93.7 97.6 97.5 97.6 3. 98.699.3 99.5 99.8 4. 93.7 97.5 98.1 98.2 5. 89.9 93.7 93.7 93.8 6. 89.697.2 97.5 97.6 Mean 0 92.7 97.2 97.6 97.7 15% Retalac 1. 75.1 89.2 95.996.0 2. 74.5 91.3 95.0 94.9 3. 85.7 99.1 100.3 100.2 4. 86.9 98.2 100.199.3 5. 84.7 93.9 94.6 94.3 6. 90.7 96.0 95.7 96.1 Mean 0 82.9 94.6 96.996.8 20% Retalac 1. 68.1 87.7 97.8 97.8 2. 62.0 83.2 95.2 96.3 3. 85.495.2 98.2 98.3 4. 76.6 94.7 97.2 96.9 5. 71.8 94.5 103.5 103.1 6. 80.695.4 99.0 98.9 Mean 0 74.1 91.8 98.5 98.6

The dissolution profile for Batch 4 is summarized in Table 5 and FIG. 2.Batch 4A shows approximately a 30% release within about 30 minutes,followed by a constant release. Complete dissolution occurred after 6hours. Batch 4B shows approximately a 23% release within about 30minutes, followed by a constant release. Complete dissolution occurredwithin 6 hours. In this example, a difference in tablet hardness resultsin a difference in release rates. FIG. 3 shows the dissolution profilesfor Batches 1-4.

TABLE 5 Concentration Hour Hour Hour Hour Hour Retardant Sample 0.5 1 24 6 (A) No. 1 30.5 47.1 70.7 96.5 96.9 30% Retalac No. 2 34.5 49.3 70.695 98 50N Hardness No. 3 27.8 42.6 64.6 90.9 95.8 30.9 46.3 68.6 94.196.9 (B) No. 4 22.5 37.1 54.9 81.2 92.5 30% Retalac No. 5 25.9 42 67.194.5 108.7 130N Hardness No. 6 23.3 36.5 57.8 87.9 101.8 23.9 38.5 59.987.9 101.0

The dissolution profile for Batch 5 is summarized in Table 6 and FIG. 4.Batch 5 represents the immediate release version of the composition. Theprofile for Batch 5 shows a 90% release within 5 minutes. Completedissolution occurred within 2 hours.

TABLE 6 Concentration Sam- min min min min min min min Retardant ple 0 515 30 45 60 120 0% Retalac 1. 92.2 96.8 96.8 96.9 97.2 2. 96.7 100.699.9 100.3 100.7 3. 94.7 100.8 100.5 100.9 101.1 4. 86.5 92.7 92.9 93.193.3 5. 85.6 91 91.7 91.4 91.8 6. 84.5 88.1 87.1 87.1 87.5 Mean 0 90.095.0 94.8 95.0 95.0 100

Table 7 below summarizes another batch, Batch 6, that was tested.

Mass Mass per Per batch Range for Weighting Material name [%] Tbl. [mg][g] variation Tolerance PE Colchicine 0.550 0.550 5.5 0.5%  Lactosemonohydrate EP 58.950 58.950 589.50 1% Pregelatinized Starch USP 7.5007.500 75.00 1% FB Hypromellose 1.000 1.000 10.00 1% 6 mPa*s EP/JP/USPWater purified * for 0.000 4.000 40.00 1% Colchicine Water purified *0.000 8.300 83.00 1% For Hypromellose Tableting mix 25% Retalac(compression strength = 55N): Lactose monohydrate EP 5.00 5.00 50.002.5%  10% 1% (Filling agent ad 100 mg per tablet) PE Retalac (50% 25.0025.00 250.00  20% 27.5% 1% Lactose/ 50% Hypromellose 4000 mPas) TalcEP/JP 1.000 1.000 10.00 1% Stearic acid 50 EP 1.000 1.000 10.00 1% Totaltablet weight: 100.000 100.000 1,000.00 Related Substances NMT 2.5%N-Deacetyl-N-formyl- NMT 1%  Colchicine (imp A) NMT 3.5% unknownimpurities Total impurities

The dissolution profile for Batch 6 is summarized in FIG. 5. Batch 6represents a sustained release version of the composition. The profilefor Batch 6 in FIG. 5 shows about a 45% release within 30 minutes, abouta 65% release in 60 minutes, and about a 80% release in 90 minutes.Complete dissolution occurs within about 2 hours.

Batch 4 was further modified by altering the concentration of retardingagent (i.e. Retalac) in the composition (Retalac 0%, 23.3%, 26.6% or30%), The dissolution profiles of the four compositions are shown inFIG. 6. As shown in FIG. 6, the composition with 23.3% Retalac showsabout a 65% release within 30 min, about a 80% release in 60 min, andabout a 90% release in 90 min. Complete dissolution occurs within about120 min. As further shown in FIG. 6, the composition with 26.6% Retalacshows about a 55% release within 30 min, about a 75% release in 60 min,and about a 85% release in 90 min. Complete dissolution occurs withinabout 180 min. As further shown in FIG. 6, the composition with 30%Retalac shows about a 40% release within 30 min, about a 55% release in60 min, and about a 70% release in 90 min. Complete dissolution occursin more than about 180 min. As further shown in FIG. 6, the compositionwith 0% Retalac (i.e., immediate release composition) shows completedissolution within about 15 min.

As mentioned previously, the release profile of the sustained releasecomposition can be changed to a specific or desired target release byadjusting the amount of retarding agent (i.e., Retalac) as well astablet hardness. The release depends upon a variety of factors,including erosion of the outer layer of colchicine (i.e., the immediaterelease portion) as well as diffusion of the inner layer of colchicine(i.e., the sustained release portion). Since the percentage ofcolchicine is low in the sustained release formulation and the tabletsare small, this balance between erosion and diffusion is very sensitiveand has to be fine-tuned to reach a very specific dissolution profile.

Example 4 Measurements of Dissolution Profiles of Sustained-ReleaseColchicine Formulations in Ethanol

To assess the potential for dose dumping, or dissolution of thecomposition in alcohol, the dissolution of the sustained releaseformulation of colchicine in ethanol was measured at various timepoints. The compositions were dissolved in 500 ml of three solutions,5%, 20% and 40% ethanol, at 37° C. and stirred continuously over aperiod of 6 hours. Samples were drawn at several time points to studythe kinetics of the dissolution process of the drug substance within thehydrophilic matrix system. Colchicine content in the samples wasanalyzed using HPLC analysis.

Example 5 Pharmacokinetic Properties of Sustained-Release ColchicineFormulations

The therapeutic effect of the sustained release formulation containingof colchicine is evaluated in a clinical study that is a multidose,randomized, cross-over study, which will evaluate bioavailability ofabout 3 different 0.50 mg sustained release formulations (e.g. TestProducts 1,2,3 and FIG. 6) of colchicine to a 0.5 mg immediate releaseformulation (control product), administered to healthy volunteers. Testproducts 1, 2, and 3 used varying levels of retarding agent (i.e.,Retalac), 23.3%, 26.6% or 30%, respectively, thereby having differentsustained release profiles. The primary aim of the study is to assesspharmacokinetics (PK) of test and control drug in blood as well as inneutrophils or leucocytes.

Research Objective:

The primary objective of this study is to compare the pharmacokineticsof the test product vs. control product of colchicine in healthy humanvolunteers. In particular, levels of colchicine in blood (hereinreferred as to blood PK), neutrophils or leucocytes (herein referred asto neutrophil PK) will be assessed upon treatment with control and testproduct.

The hypothesis tested is that administration of an equal amount ofcolchicine in form of a sustained release tablet leads to lower peaklevels (Cmax), while maintaining equal absolute bioavailability (areaunder the curve, AUC). Colchicine concentrations in neutrophils aremeasured as it is generally recognized that neutrophils whichreconstitute 60-70% of leukocytes, play a central role in inflammatoryresponses in general and are thought to be major players in severaldiseases where colchicine is used as treatment. Therefore for thepurpose of this experiment, either leucocytes or neutrophils may beanalyzed. Hence, the term neutrophils as used herein also refers to, ifused, leucocytes. As colchicine is known to preferentially accumulate inneutrophils and inhibit many of their pro-inflammatory functions, theyare thought to be a major target of colchicine therapy. Therefore it isof special interest to know whether similar concentrations of colchicineare reached in isolated neutrophils or in leukocytes which would giveinformation on potential bioequivalence. Therefore, blood will be drawnin various time points over the course of the study to check colchicineconcentrations in blood and neutrophils.

General Study Design:

This study is designed as a randomized, cross-over study. There will be3 groups of patients (n=3× at least 8). Group 1 will receive control ortest drug for about 8-14 days. After a wash out period, they willreceive test drug 1 for about 8-14 days. Group 2 will receive thecontrol drug for the same time. After a wash out period, they willreceive test drug 2 for the same time. Group 3 will receive the controldrug for the same time. After a wash out period, they will receive testdrug 3 for the same time. The study participants are treated on anin-patient basis for the first 24 h and on an out-patient basis for theremaining time. A sufficiently long wash-out period lies between the twotrials.

Subject Participation:

There will be 3 groups of patients (n=3× at least 8). For each testdrug, healthy volunteers will be randomized to one drug for the firstround. After a sufficient wash out period, the same subjects willreceive the control drug.

Study Duration:

The study drug is administered at a single dose/day for about 8-14 daysconsecutive days. The study consists of 24 h blood PK (high frequencydata collection). Neutrophil PK is analysed in intervals that allow forconclusive determination of colchicine levels in the latter over theduration of the experiment.

Treatment Regimen:

Below is an example of what the treatment regime may look like.

Cycle 1 Wash out Cycle 2 Group 1 14 days 14 days 14 days Control or test1 Test 1 or control Group 2 14 days 14 days 14 days Control or test 2Test 2 or control Group 3 14 days 14 days 14 days Control or test 3 Test3 or control

Research Techniques and Data Analysis:

Analytical chemistry techniques (HPLC) or immunological techniques(radioimmunoassay) may be utilized for the assessment of colchicine andoptionally, its metabolites. Collected data is analyzed by adequate datamanagement and statistics software.

Subject Population:

The study population consists of male healthy volunteers (n=5-10/group).For inclusion in the study, the patient must be 25-40 years of age; notless than 60 kg and not more than 120 kg body weight; healthy; no majorcompeting comorbidities or contraindication to colchicine therapy;willing to provide consent and be randomized into the study. Patientswho meet the following criteria will be excluded: ongoing therapy withother anti-inflammatory/immunosuppressive drugs; treatment with drugswith known drug interactions with colchicine; renal/hepatic impairment;known hypersensitivity to colchicine.

Treatment Schema:

The drug is given once a day in the morning.

Data Collection Schema:

For blood PK, blood will be collected over a period of 24 h at thebeginning the study in short intervals (sufficient time points toestablish pharmacokinetic data, e.g.: −1, +0.5 h, 1 h, 1.5 h, 2 h, 3 h,4 h, 5 h, 7 h, 10 h, 12 h, 15 h and 24 h (before next application).Additional time points may be 24 h, and 10 days after drug withdrawal atthe end of the study to examine the wash out phase of the drug. PKanalysis includes colchicine blood concentrations. Adequate techniquesfor the isolation of blood and quantification of colchicine are applied.

For neutrophil PK, neutrophils will be isolated or purified from rawblood from several time points. Neutrophils will be collected at thebeginning the study as well as at least once at the end of the study. PKanalysis includes colchicine concentrations in isolated neutrophils.

Results: The results are shown in FIGS. 7-9. FIGS. 7A-7D show plasmacolchicine levels (ng/mL) as a function of time (hrs) in the immediaterelease formulation (FIG. 7A) as compared to the sustained releaseformulations (FIGS. 7B, 7C and 7D). The immediate release formulation ofFIG. 7A has a Cmax of 1.77+/−0.8 ng/mL, an AUC (o-t) of 8.08+/−2.9 ng/mLand a Tmax of 0.83+/−0.2 hr. The sustained release formulation of FIG.7B has a Cmax of 1.56+/−0.4 ng/mL, an AUC (o-t) of 7.94+/−0.9 ng/mL anda Tmax of 1.47+/−0.2 hr. The sustained release formulation of FIG. 7Chas a Cmax of 1.56+/−0.4 ng/mL, an AUC (o-t) of 7.94+/−0.9 ng/mL and aTmax of 1.47+/−0.2 hr. The sustained release formulation of FIG. 7D hasa Cmax of 0.91+/−0.3 ng/mL, an AUC (o-t) of 5.04+/−2.3 ng/mL and a Tmaxof 1.89+/−0.4 hr. FIG. 8 shows the overlapping profiles of the immediaterelease formulation and the three sustained release profiles. As can beseen, there is less inter-subject variation in plasma levels, lower Cmaxand similar AUC for the sustained release formulation of FIG. 7B whencompared to the immediate release formulation. Since the colchicineconcentration on plasma increases and decreases more steadily and in amore controlled way, and the variability of colchicine levels in plasmafrom patient to patient is less, the safety and efficacy profile is morepredicable. As a result, there will likely be fewer adverse side effects(e.g., gastrointestinal side effects) and/or reduced risk of toxicity(e.g., due to drug-drug interactions or co-morbidities such as renaland/or hepatic impairment).

FIG. 9 shows the levels of colchicine in neutrophils on Day 1 and Day 10in the immediate release formulation and the three sustained releaseformulations. As can be seen, the levels of colchicine increase from Day1 to Day 10, suggesting that colchicine accumulates in neutrophils overtime. The results further show that the levels in neutrophils aresimilar after 10 days regardless of the formulation, suggesting that thetherapeutic effect will be equal for the tested sustained release andimmediate release formulations (as the site of action of colchicine isneutrophils).

Example 6 Therapeutic Effects of an Immediate Release Formulation inPatients with Cardiovascular Disease

To assess the therapeutic effects of an immediate release formulation inpatients with cardiovascular disease, a prospective randomized observerblinded end-point trial was conducted to determine whether adding 0.5mg/day of colchicine to standard secondary prevention therapiesincluding aspirin and high dose statins reduces the risk ofcardiovascular events in patients with objectively diagnosed andclinically stable coronary disease. This study is described inPCT/AU2013/001261 and is hereby incorporated in its entirety byreference.

Study Conduct and Design:

The LoDoCo Trial was conducted under the auspices of the Heart ResearchInstitute of Western Australia. It was designed by the principalinvestigators, registered with the Australian Clinical Trial Registry(12610000293066), and received ethics approval from the Human ResearchEthics Committee at Sir Charles Gairdner Hospital Perth WesternAustralia in July 2008. There was no external funding source.

The study had a prospective randomized, open, blinded end-point design.Eligible consenting patients with established coronary diseasepresenting for routine clinical review were randomized to receivecolchicine 0.5 mg/day or no colchicine without any other change to theirmedical therapy. All outcomes were evaluated by an experiencedadjudicator blinded to the treatment allocation.

Study Size and Eligibility:

It was planned to recruit a study population that would include 250patients, 28 randomized to the control group and 250 patients randomizedto treatment who were tolerant of colchicine for at least 4 weeks afterthe date of their randomization. Patients were eligible for inclusion ifthey met each of the following criteria: 1) angiographically provencoronary disease; 2) aged 35 to 85 years; 3) clinically stable for atleast 6 months, 4) no major competing co-morbidities or contraindicationto colchicine therapy, 5) considered to be compliant with therapy andattending routine cardiology follow up appointments, and 6) willing tobe consented and randomized into the study. Patients with a history ofbypass surgery were only eligible if they had undergone bypass surgerymore than 10 years before, or had angiographic evidence of graft failureor had undergone stenting since their bypass surgery. All patientssigned informed consent before randomization.

Randomization:

The randomization sequence was computer generated, kept concealed fromthe investigators at all times and was managed by a research assistantwho had no involvement in the evaluation or management of studypatients. Once the assistant received the consent form, the patients'demographic data were entered into the data base and the investigatorsand patients were advised in writing of the treatment group to which thepatient had been assigned. Despite electing to use the lowest dose ofcolchicine available, it was anticipated that a number of patients wouldwithdraw from therapy early after randomization due to gastrointestinalside effects. In order to ensure that the requisite number of patientsin the treatment arm were actually tolerant of treatment, the protocolallowed for the research assistant to assign a newly recruited patientto treatment if a patient discontinued colchicine due to side effects inthe first month. Patients who were intolerant to therapy remained in thestudy, and were followed in the usual manner and included in the primaryintention to treat analysis.

Intervention:

Patients randomized to active treatment were given a prescription forcolchicine 0.5 mg daily by their referring cardiologist. The drug wasdispensed by their usual chemist, and if requested, patients werereimbursed for the cost of these scripts. All other treatments werecontinued as usual.

Follow-Up and Definition of Clinical Outcomes:

Patient compliance with treatment and outcome data were collected atroutine follow up visits and at the time of any unplanned hospitaladmission. An acute coronary syndrome (ACS) was defined as either (a)Acute Myocardial Infarction (AMI), as evidenced by acute ischemic chestpain associated with a rise in serum troponin above the upper limit ofnormal or (b) Unstable Angina (UA), as evidenced by a recentacceleration of the patient's angina unassociated with a rise in serumtroponin but associated with angiographic evidence of a change in thepatient's coronary anatomy. (Unstable Angina Braunwald classificationtypes IB and IIB). The ACS was characterized as being stent-related ifthere was evidence of significant in-stent stenosis or acute stentthrombosis. Out of Hospital Cardiac Arrest was defined as either asudden death as evidenced on the patient's death certificate, or anon-fatal out of hospital cardiac arrest, defined as a recovery fromsudden collapse associated with documented asystole, ventriculartachycardia or ventricular fibrillation. Noncardioembolic ischemicstroke was defined as CT or MRI proven ischemic stroke adjudged by thetreating neurologist as not being due to atrial fibrillation orintracranial hemorrhage.

The primary efficacy outcome was the composite, ACS, fatal or non-fatalout of hospital cardiac arrest or non-cardio-embolic ischemic stroke.Secondary outcomes were (a) individual components of the primaryoutcome, and (b) the components of ACS unrelated to stent disease.

Timelines:

The pre-specified study duration was a minimum follow up of two years inall patients. Accordingly the study was closed on May 31, 2012. DuringMay, all living patients were contacted by phone to collect complianceand outcome data from the last date of follow-up. Final outcome datawere available in all patients and no patients were lost to follow up.

Statistical Power:

Assuming that the control group had a combined event rate (ACS, out ofhospital cardiac arrest or non cardio-embolic-ischemic stroke) of 8%, anaccrual interval of 2 years and a follow-up after the accrual intervalof 2 years, the planned sample size provided >80% power to detect ahazard ratio of <0.50 based on a two sided significance level of 5%.

Data Analysis:

Summary statistics, including mean and standard deviation werecalculated for all baseline characteristics by treatment arm. All timeto event outcomes were calculated in days by subtracting the date ofrandomization from either: (1) the date of event or death; or (2) thetrial termination date for those patients not experiencing the definedevent. As pre-specified, the primary efficacy analysis was based on theintention-to-treat principle. The intention-to-treat analysis includedall randomized subjects and all events during the time fromrandomization to the trial termination. Trial termination date was fixedas May 31, 2012. A secondary pre-specified on-treatment analysis wasalso performed, based on patients who were both tolerant and compliantto therapy beyond the first month of randomization. All events duringthe time from randomization until non-compliance with colchicinetreatment regimen were included in this analysis.

The time-to-first-event for all outcomes is presented using aKaplan-Meier plot. The primary efficacy outcome was analyzed using a coxproportional hazards model including treatment group coded as control orcolchicine. The secondary outcomes were analysed similarly. In addition,the primary analysis was stratified by gender, age, diagnosis ofdiabetes, past myocardial infarction, unstable angina, coronary bypasssurgery, coronary angioplasty, and therapy with aspirin, clopidogrel orboth, high dose statin therapy (defined as a dose of statin equivalentto atorvastatin of 40 mg or more), beta blockers, calcium blockers andACE inhibitors.

Results:

Between August 2008 and May 2010, 901 patients with stable coronarydisease attending for routine out-patient cardiology review wereassessed for eligibility for the study. Of these, 297 (33%) did not meetthe entry criteria, 72 (8%) declined to participate and 532 (59%) wereenrolled into the study, 250 of whom were randomized to the controlgroup and 282 to treatment. Of those randomized to treatment 32 (11%)reported early intolerance, due to gastrointestinal side effects, and 7patients subsequently reported that they chose not start therapy. All532 randomized patients were followed for the duration of the studyperiod which ranged from a minimum of 24 to a maximum of 44 months.Median follow up was 36 months.

Outcomes:

A primary outcome occurred in 55/532 patients, including 15/282 (5.3%)patients assigned to colchicine treatment, and 40/250 (16%) patientsassigned to the control group [hazard ratio 0.33, 95% CI; 0.18-0.59;p<0.001, number needed to treat 11). A sensitivity analysis wasperformed for the primary outcome, adjusting for the usage of calciumchannel blockers and beta blocker therapy. These results were consistentwith the primary analysis.

The effect of colchicine on the primary outcome was evident early andthe benefits of colchicine continued to accrue throughout the follow upperiod. There was no evidence of differential treatment effects based onany of the clinical or therapeutic variables.

The reduction in the primary outcome was largely driven by the reductionin the number of patients presenting with an ACS, (13/282 (4.6%) vs.34/250 (13.4%), hazard ratio 0.33; 95% CI; 0.18-0.63; p<0.001). Out ofhospital cardiac arrest and non-cardio-embolic ischemic stroke wereinfrequent but were also reduced in the treatment group.

Of the 47 patients who presented with an ACS, the event was stentrelated in 8 (17%) (2 in each group had evidence of acute stentthrombosis and 2 in each group had evidence of significant in-stentstenosis). Further analysis confirmed that patients randomized totreatment were less likely to present with an ACS unrelated to stentdisease (9/282 (3.2%) vs. 30/250 (12%) hazard ratio 0.26, 95% CI;0.12-0.55; p<0.001), be it associated with an AMI (4/282 (1.4%) vs.14/250 (5.6%) hazard ratio 0.25, 95% CI; 0.08-0.76; p=0.014) or UA(5/282 (1.8%) vs. 16/250 (6.4%) hazard ratio 0.27, 95% CI; 0.10-0.75;p=0.011).

Of 39 patients randomized to treatment who did not receive therapybeyond the first month due to early intolerance or non-compliance, 4(10%) presented with an ACS due to acute stent thrombosis (n=1) and UA(n=3). Patients who were both compliant and tolerant to therapy beyondthe first month of randomization had significantly fewer events than thecontrol patients (11/243 (4.5%) vs. 40/250 (16%) hazard ratio 0.29, 95%CI; 0.15-0.56; p<0.001). The results of all on-treatment analyses wereconsistent with those based upon the intention to treat analyses.

Ten patients in the control group died compared with 4 patients in thecolchicine group. Of the 10 controls, 5 died of presumed cardiac cause;2 following an out-of-hospital cardiac arrest, 2 from cardiogenic shockfollowing myocardial infarction, and 1 following bypass surgery. All 4patients in the colchicine group died of non-cardiac causes.

This trial demonstrates that the addition of colchicine 0.5 mg/day tostandard therapy in patients with stable coronary disease significantlyreduces the risk of a cardiovascular event, including an ACS, out ofhospital cardiac arrest and non-cardio-embolic ischemic stroke. Thebenefits of colchicine were achieved on a background of widespread useof effective secondary prevention strategies, including high dosestatins, as evidenced by the low event rate in the control group. Theeffect of adding colchicine became evident early, continued to accrueover time and was largely driven by a reduction in ACS unrelated tostent disease.

Example 7 Dose Adjustments of Sustained Release Colchicine Formulations

To determine the proper dose amounts, the sustained released formulationmay be administered to patient populations with different body weights.Assuming that a 0.5 mg tablet gives a certain plasma level of colchicinein average weight patients and that this particular level should bereached in every patient to achieve efficacy, one can perform PKanalysis of a 0.5 mg tablet in different weight groups. It is expectedthat levels in blood (Cmax and AUC) in heavy patients are lower, whichindicates that dose adjustments towards higher doses is necessary.

Research Objective:

The primary objective of this study is to compare the pharmacokineticsof a 0.5 mg colchicine tablet in healthy human volunteers of at least 2different body weight groups. In particular, levels of colchicine inblood will be assessed upon treatment. The hypothesis tested is thatadministration of an equal amount of colchicine in leads to differentcolchicine levels depending to body weight. Body weight and colchicinelevels are inverse correlated.

General Study Design:

This study is designed as a randomized, cross-over study. n=at least 8subjects are selected according to body weight. If 2 groups are made,then 50% will be of low weight (e.g. below 65 kg) and 50% of high weight(e.g. above 90 kg).

Study Duration:

The study drug is administered once. The study consists of 24 h blood PK(high frequency data collection).

Research Techniques and Data Analysis:

Analytical chemistry techniques (HPLC) or immunological techniques(radioimmunoassay) may be utilized for the assessment of colchicine.Collected data is analyzed by adequate data management and statisticssoftware.

Subject Population:

The study population consists of male healthy volunteers. For inclusionin the study, the patient must be 25-40 years of age; not less than 50kg and not more than 120 kg body weight; healthy; no major competingcomorbidities or contraindication to colchicine therapy; willing toprovide consent and be randomized into the study. Patients who meet thefollowing criteria will be excluded: ongoing therapy with otheranti-inflammatory/immunosuppressive drugs; treatment with drugs withknown drug interactions with colchicine; renal/hepatic impairment; knownhypersensitivity to colchicine.

Treatment Schema:

The drug is given once in the morning of the study.

Data Collection Schema:

For blood PK, blood will be collected over a period of 24 h at thebeginning the study in short intervals (sufficient time points toestablish pharmacokinetic data, e.g: −1, +0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4h, 5 h, 7 h, 10 h, 12 h, 15 h and 24 h (before next application).Additional time points may be 24 h, and 72 h after drug withdrawal atthe end of the study to examine the wash out phase of the drug.

Example 8 Non-Clinical Pharmacokinetics Study of Sustained Release (SR)Versus Immediate Release (IR) of Colchicine

A sufficiently high number of adequate laboratory animals (e.g. rodentssuch as mice or rats, at least 5 animals per group) is used in thisexperiment. The control drug is an IR tablet of colchicine. The testdrug is an SR tablet of colchicine.

The control group of mice is given a single first dose of IR colchicinein a strength which lies in the therapeutic window (the plasma levelrange of colchicine where a therapeutic effect can be observed. It willbe determined and set arbitrary in the used laboratory animal species asa maximum level sufficiently below the LD50 and a minimum levelapproximately 6 fold less than the maximum level). The test group isgiven a single first dose of SR colchicine in the same strength. Bloodis drawn from both groups at time points 0.25 h, 0.5 h, 0.75 h, 1 h, andthen hourly for 12 h and every 3 hours until 24 h. Simultaneously, fecesare drawn from the cages of test and control animals after 3 h, 6 h, 12h and 24 h (test and control animals must not be put in the same cages).

Primary Readout:

Colchicine plasma levels. Secondary readout: Determination of colchicineand its metabolites in feces to see whether enterohepatic recirculationoccurs to a lesser extent in test animals than in control animals. Bloodsamples are processed and colchicine levels in blood plasma are measuredwith HPLC analysis or an equivalent quantitative method.

Results: The experiment is expected to show that the total absorption ofcolchicine (area under the curve) is similar in test and controlanimals. However, in control animals, colchicine absorption peaks at ca.1 h post administration and then rapidly declines. After 2-3 h,colchicine levels are below the therapeutic range. Also, due toenterohepatic recirculation of un-metabolized colchicine, re-absorptionoccurs which manifests in the characteristic secondary peak after 3-6 h.

However, in test animals (SR), colchicine levels will rise more slowlyand do not reach peak levels of colchicine as observed in controlanimals. The peak levels are observed after 3-8 h and then slowlydecline. Therapeutic colchicine levels remain for at least 12 h. Due tothe more complete metabolism of colchicine in the liver, enterohepaticrecirculation occurs to a lesser extent and no secondary peak can beobserved. As a secondary readout, feces of test and control animals areinvestigated to see whether enterohepatic recirculation occurs to alesser extent in test animals than in control animals. It can be shownthat the ratio of unchanged colchicine vs. metabolized colchicine ishigher in control than in test animals. Thus, SR colchicine results in amore complete metabolism of colchicine in the liver.

Example 9 Non-Clinical Safety Study of SR Versus IR of Colchicine

A sufficiently high number of adequate laboratory animals (e.g. rodentssuch as mice or rats, at least 5 animals per group) is used in thisexperiment. The control drug is an IR tablet of colchicine. The testdrug is an SR tablet of colchicine.

The control group of mice is given one dose IR colchicine/day in astrength which lies in the therapeutic window (the plasma level range ofcolchicine where a therapeutic effect can be observed. It will bedetermined and set arbitrary in the used laboratory animal species as amaximum level sufficiently below the LD50 and a minimum levelapproximately 6 fold less than the maximum level). The test group isgiven one dose SR colchicine/day in the same strength. Alternatively,test and control animals are given a total of two doses/day, one in themorning and one in the evening. The duration of the experiment is 2weeks.

Primary readout is the incidence of gastrointestinal adverse events (e.gcramps, diarrhea etc.). This is evaluated in 3 ways. Daily, behaviour ofthe tested animals is observed with a predetermined standardized methodwhere signs of illness are investigated. Secondly, feces areinvestigated daily for morphology as well as presence of apoptoticepithelial cells. Thirdly, individual animals are sacrificed atpredetermined time points and the small and big intestine isinvestigated for histopathological signs of colchicine toxicity.

Results: Over the course of the experiment, it can be expected that thecontrol animals suffer from more gastrointestinal adverse events thanthe test animals. Thus, SR colchicine exhibits a better safety profilethan IR colchicine.

Example 10 Clinical Safety Study of SR Versus IR of Colchicine

If laboratory animals turn out to be inadequate for the investigation ofadverse events related to colchicine administration, an equivalentexperiment is carried out in humans. It is carried out in healthy adultvolunteers or additionally in patients in need of colchicine. Asufficiently high number of humans is used to reach statisticalsignificance. The test and control medication consists of a SR or IRoral solid dosage form of colchicine in strength of 0.25-1 mg. Asufficiently high dose is administered to reach therapeutic levels ofcolchicine. Alternatively to once daily administration, the tested drugsare given twice daily as indicated in Example 3, above. Alternatively,to control placebo effect, a placebo group is included in bothexperimental settings. The duration of the experiment is between 2 weeksand 1 month.

Many modifications and other embodiments of the inventions set forthherein will come to mind to one skilled in the art to which theseinventions pertain having the benefit of the teachings presented in theforegoing descriptions and the associated drawings. Therefore, it is tobe understood that the inventions are not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended claims and listof embodiments disclosed herein. Although specific terms are employedherein, they are used in a generic and descriptive sense only and notfor purposes of limitation.

What is claimed is:
 1. A method of treating and/or preventingcardiovascular disease in a patient, the method consisting of orallyadministering a sustained release formulation comprising not more than0.60 mg colchicine to a human patient, wherein the colchicine isadministered once a day, thereby treating and/or preventing thecardiovascular disease in the patient.
 2. The method of claim 1, whereinthe cardiovascular disease is selected from the group consisting ofacute pericarditis, recurrent pericarditis, post-pericardiotomy syndrome(PPS) and cardiovascular events in patients with stable coronarydisease.
 3. The method of claim 1, wherein the colchicine isadministered in combination with conventional therapy for the long-termprevention of an acute cardiovascular event in patients with establishedstable coronary disease.
 4. The method of claim 3, wherein said acutecardiovascular event is acute coronary syndrome, out-of-hospital cardiacarrest or noncardioembolic ischemic stroke.
 5. The method of claim 3,wherein the conventional therapy includes the administration of acolchicine-compatible statin selected from the group consisting ofatorvastatin, rosuvastatin, simvastatin and pravastatin, a derivative ora salt thereof.
 6. The method of claim 1, wherein colchicine is includedin an amount of 0.55 mg.
 7. A method of treating a patient having acardiovascular disease, the method consisting of: orally administering asustained release formulation comprising not more than 0.60 mgcolchicine to a human patient once daily, wherein the sustained releaseformulation provides a maximum colchicine blood plasma concentration(Cmax) in a range of about 1.0 to about 2.0 ng/mL, and a time after thefirst administration at which Cmax is reached (Tmax) of about 1.2 toabout 2.0 hr.
 8. The method of claim 7, wherein the sustained releaseformulation further provides an area under the curve of colchicineplasma concentration versus time from time 0 to time t (AUC0-t), where tis the last time point with a measurable colchicine plasmaconcentration, in a range of about 7 to about 9 ng-hr/mL.
 9. The methodof claim 7, wherein colchicine is included in an amount of 0.55 mg. 10.The method of claim 7, wherein the maximum colchicine blood plasmaconcentration (Cmax) is 1.77+/−0.8 ng/mL and/or the time after the firstadministration at which Cmax is reached (Tmax) 0.83+/−0.2 hr.
 11. Themethod of claim 7, wherein the area under the curve of colchicine plasmaconcentration versus time from time 0 to time t (AUC0-t), where t is thelast time point with a measurable colchicine plasma concentration, is8.08+/−2.9 ng/mL.
 12. The method of claim 7, wherein the cardiovasculardisease is selected from the group consisting of acute pericarditis,recurrent pericarditis, post-pericardiotomy syndrome (PPS) andcardiovascular events in patients with stable coronary disease.
 13. Themethod of claim 7, wherein the colchicine is administered in combinationwith conventional therapy for the long-term prevention of an acutecardiovascular event in patients with established stable coronarydisease.
 14. The method of claim 13, wherein said acute cardiovascularevent is acute coronary syndrome, out-of-hospital cardiac arrest ornoncardioembolic ischemic stroke.
 15. The method of claim 13, whereinthe conventional therapy includes the administration of acolchicine-compatible statin selected from the group consisting ofatorvastatin, rosuvastatin, simvastatin and pravastatin, a derivative ora salt thereof.
 16. The method of claim 7, wherein the sustained releaseformulation releases at least about 80% of the colchicine in vitrowithin 1.5 hours.
 17. The method of claim 7, wherein the sustainedrelease formulation releases at least about 55% of the colchicine invitro within the first 30 minutes.
 18. The method of claim 7, whereinthe sustained release formulation further comprises a retarding agentand at least one pharmaceutically acceptable excipient.
 19. The methodof claim 18, wherein the retarding agent is selected from the groupconsisting of cellulose ethers, cellulose esters, acrylic acidcopolymers, waxes, gums, glyceryl fatty acid esters and sucrose fattyacid esters.
 20. The method of claim 18, wherein the retarding agentcomprises hypromellose.
 21. The method of claim 18, wherein theretarding agent is included in an amount between about 5 wt % and about40 wt % of the formulation.
 22. The method of claim 18, wherein thepharmaceutically acceptable excipient is selected from the groupconsisting of a binder, a filling agent, a glidant, and a lubricant, ora combination thereof.
 23. The method of claim 22, wherein thepharmaceutically acceptable excipient is a binder selected from thegroup consisting of starches, gelatin, polyvinylpyrrolidone, cellulosederivatives, polyvinyl alcohol and mixtures thereof.
 24. The method ofclaim 23, wherein the cellulose derivative is selected from the groupconsisting of hydroxypropyl methylcellulose (HPMC) and hydroxypropylcellulose (HPC).
 25. The method of claim 22, wherein thepharmaceutically acceptable excipient is a filling agent selected fromthe group consisting of sucrose, lactose monohydrate, trehalose,maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone,alginic acid, sodium alginate, methacrylic acid DVB, cross-linked PVP,microcrystalline cellulose, polacrilin potassium, sodium starchglycolate, starch, pregelatinized starch, and combinations thereof. 26.The method of claim 25, wherein the total amount of filling agent in theformulation is between about 5.0 wt % and 90.0 wt % of the formulation.27. The method of claim 22, wherein the pharmaceutically acceptableexcipient is a glidant selected from the group consisting of colloidalsilicon dioxide, magnesium trisilicate, powdered cellulose, talc, andtribasic calcium phosphate.
 28. The method of claim 27, wherein totalamount of glidant in the formulation is between about 0.5 wt % to about5 wt % of the formulation.
 29. The method of claim 22, wherein thepharmaceutically acceptable excipient is a lubricant selected from thegroup consisting of glyceryl behenate, stearic acid, hydrogenatedvegetable oils, stearyl alcohol, leucine, polyethylene glycol, magnesiumstearate, glyceryl monostearate, polyethylene glycol, ethylene oxidepolymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodiumoleate, sodium stearyl fumarate, DL-leucine, and colloidal silica. 30.The method of claim 29, wherein the lubricant is included in an amountbetween about 0.5 wt % to about 5 wt % of the formulation.